Figure 3 - uploaded by Paul Nghiem
Content may be subject to copyright.
Culture of Merkel cell carcinoma (MCC) tumors in IL-2 and IL-15 leads to T-cell activation, proliferation, and expansion of CD8 T cells. (a) T cells from tumors treated for 1 week with IL-2 and IL-15 showed marked upregulation of CD69 and CD25, increased percentages of CD25+FOXP3--activated effector T cells, and reduced percentages of CCR7+/L-selectin+ central memory T-cell (TCM). The mean and SEM from seven tumors of parameters that (b) changed or (c) remain unchanged after 1 week of IL-2 and IL-15 treatment are shown. The percentages of cutaneous lymphocyte antigen+ (CLA+) skin-homing and FOXP3+ regulatory T cells were not altered by cytokine treatment of tumors. (d) By 3 weeks of culture, CD8+ T cells predominated and marked T-cell proliferation was evident, as indicated by the proliferation marker Ki-67. All histograms are gated to show CD3+ T cells. FSC-H, forward scatter (height); SSC-A, side scatter (area); n.s., not significant.Download Power Point slide (421 KB)
Source publication
Merkel cell carcinomas (MCC) are rare but highly malignant skin cancers associated with a novel polyomavirus. MCC tumors were infiltrated by T cells, including effector, central memory and regulatory T cells. Infiltrating T cells showed markedly reduced activation as evidenced by reduced expression of CD69 and CD25. Treatment of MCC tumors in vitro...
Contexts in source publication
Context 1
... cytokines including IL-2 and IL-15 have been used in vitro to expand TILs with antitumor activity from malignant melanoma (Mueller et al., 2008;Rosenberg et al., 2011). We expanded T cells from MCC tumors with IL-2 and IL-15 for one week and observed marked increases in cell size and granularity, enhanced activation as evidenced by increased expression of both CD69 and CD25, increased numbers of CD25 + FOXP3 − activated effector T cells, and reduced percentages of CCR7 + /L-selectin + T CM (Figure 3a, b). After three weeks of stimulation, we observed T cell proliferation, particularly CD8 T cells, as indicated by the proliferation marker Ki-67 ( Figure 3d). ...
Context 2
... expanded T cells from MCC tumors with IL-2 and IL-15 for one week and observed marked increases in cell size and granularity, enhanced activation as evidenced by increased expression of both CD69 and CD25, increased numbers of CD25 + FOXP3 − activated effector T cells, and reduced percentages of CCR7 + /L-selectin + T CM (Figure 3a, b). After three weeks of stimulation, we observed T cell proliferation, particularly CD8 T cells, as indicated by the proliferation marker Ki-67 ( Figure 3d). In contrast to these population shifts, we found no changes in the percentages of CLA + skin-homing or FOXP3 + Tregs (Figure 3c). ...
Context 3
... three weeks of stimulation, we observed T cell proliferation, particularly CD8 T cells, as indicated by the proliferation marker Ki-67 ( Figure 3d). In contrast to these population shifts, we found no changes in the percentages of CLA + skin-homing or FOXP3 + Tregs (Figure 3c). Further studies demonstrated that IL-15 was critical for enhancing T cell activation and proliferation, as these were mostly unchanged by IL-2 treatment alone (Suppl. ...
Citations
... For instance, factors such as nutrition restrictions, hypoxia, and immunosuppressive cells and signals render the TME immunosuppressive [59,60]. T cell exhaustion is an important immune escape mechanism in MCC: a significant proportion of TILs express PD-1 and TIM-3, which are not only regarded as the exhaustion markers, but actually promote T-cell dysfunction [52,61]. Activation and proliferation of T cells are inhibited through PD-1 signaling. ...
... On the basis of the observations that MCCs are immunogenic and TILs expedite the activation and exhaustion markers PD-1 on the one hand and PD-L1 on tumor and stromal cells on the other [61,72,73], it was postulated early on that this tumor entity should be well susceptible to immune checkpoint inhibitor (ICI) therapy, especially antibodies that block the PD-1/PD-L1 signaling pathway. However, the economic viability of introducing a therapy in a rare type of cancer is relatively limited; thus, it took some time for this hypothesis to be put to the test. ...
Merkel cell carcinoma (MCC) is a rare skin cancer characterized by neuroendocrine differentiation. Its carcinogenesis is based either on the integration of the Merkel cell polyomavirus or on ultraviolet (UV) mutagenesis, both of which lead to high immunogenicity either through the expression of viral proteins or neoantigens. Despite this immunogenicity resulting from viral or UV-associated carcinogenesis, it exhibits highly aggressive behavior. However, owing to the rarity of MCC and the lack of epidemiologic registries with detailed clinical data, there is some uncertainty regarding the spontaneous course of the disease. Historically, advanced MCC patients were treated with conventional cytotoxic chemotherapy yielding a median response duration of only 3 months. Starting in 2017, four programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors—avelumab, pembrolizumab, nivolumab (utilized in both neoadjuvant and adjuvant settings), and retifanlimab—have demonstrated efficacy in treating patients with disseminated MCC on the basis of prospective clinical trials. However, generating clinical evidence for rare cancers, such as MCC, is challenging owing to difficulties in conducting large-scale trials, resulting in small sample sizes and therefore lacking statistical power. Thus, to comprehensively understand the available clinical evidence on various immunotherapy approaches for MCC, we also delve into the epidemiology and immune biology of this cancer. Nevertheless, while randomized studies directly comparing immune checkpoint inhibitors and chemotherapy in MCC are lacking, immunotherapy shows response rates comparable to those previously reported with chemotherapy but with more enduring responses. Notably, adjuvant nivolumab has proven superiority to the standard-of-care therapy (observation) in the adjuvant setting.
... CLA, which guides memory T cells back to the skin, has been associated with higher total T cell infiltration and better clinical outcomes in MCC. 61 In contrast, we also identified a CD39 + CD103 + CD8 T cell population that is transcriptionally distinct and inversely correlated with patient response to pembrolizumab. CD103, a resident memory T cell marker that also mediates cell binding to epithelial and endothelial cells, has also been implicated as a marker for tumor reactivity in TILs 19,62,63 and in blood 64 in the context of other tumor types. ...
Merkel cell carcinoma is a skin cancer often driven by Merkel cell polyomavirus (MCPyV) with high rates of response to anti-PD-1 therapy despite low mutational burden. MCPyV-specific CD8 T cells are implicated in anti-PD-1-associated immune responses and provide a means to directly study tumor-specific T cell responses to treatment. Using mass cytometry and combinatorial tetramer staining, we find that baseline frequencies of blood MCPyV-specific cells correlated with response and survival. Frequencies of these cells decrease markedly during response to therapy. Phenotypes of MCPyV-specific CD8 T cells have distinct expression patterns of CD39, cutaneous lymphocyte-associated antigen (CLA), and CD103. Correspondingly, overall bulk CD39⁺CLA⁺ CD8 T cell frequencies in blood correlate with MCPyV-specific cell frequencies and similarly predicted favorable clinical outcomes. Conversely, frequencies of CD39⁺CD103⁺ CD8 T cells are associated with tumor burden and worse outcomes. These cell subsets can be useful as biomarkers and to isolate blood-derived tumor-specific T cells.
... We also identified a cluster of CD8+ T cells that amplified during the RespD376 and showed both exhaustion and proliferation phenotypes. This was consistent with the previous finding that infiltrating T cells were usually characterized by an exhausted phenotype [33,34]. The impact of exhausted phenotype T cell effectors on patients may be greater than the activity of their CD8+ T cells expanded in vitro, leading to the gradual depletion of these T cells used for immunotherapy and loss of their therapeutic efficacy. ...
Purpose
Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma originating in the skin. Studies are needed to determine the mechanisms of immune escape in patients with MCC, and malignant cell conditions that promote immune evasion.
Methods
We used Single-cell RNA sequencing (scRNA-seq) to determine cellular features associated with MCC disease trajectory. A longitudinal multi-omics study was performed using scRNA-seq data of peripheral blood harvested from four-time points. Six major cell types and fifteen cell subgroups were identified and confirmed their presence by expression of characteristic markers. The expression patterns and specific changes of different cells at different time points were investigated. Subsequently, bulk RNA data was used to validate key findings.
Results
The dynamic characteristics of the cells were identified during the critical period between benign improvement and acquisition of resistance. Combined with the results of the validation cohort, the resistance program expressed in the relapse stage is mainly associated with T cell exhaustion and immune cell crosstalk disorder. Coinciding with immune escape, we also identified a decrease non-classical monocytes and an expansion of classical monocytes with features of high inflammation and immune deficiency.
Conclusion
Changes in cellular status, such as depletion of T cells and dysregulation of B cell proliferation and differentiation, may lead to drug resistance in MCC patients. Meanwhile, the widespread decreased antigen presentation ability and immune disorders caused by deletion of MHC class II gene expression should not be ignored.
... Because LT can reinitiate DNA replication off of the integrated viral origin (7), leading to replication fork collision and DNA fragmentation, the nascent cancer cell survives because another, independent mutation is present in the LT gene to truncate its C-terminal helicase domain preventing LT-dependent DNA replication (7,14). It is unknown which mutation comes first, LT gene truncation (7) or virus integration (11), but both are required, together with loss of effective cytotoxic T lymphocyte responses against early viral antigens (15,16), for emergence of this virus-driven cancer (8). ...
Cellular eukaryotic replication initiation helicases are first loaded as head-to-head double hexamers on double-stranded (ds) DNA origins and then initiate S-phase DNA melting during licensed (once per cell cycle) replication. Merkel cell polyomavirus (MCV) large T (LT) helicase oncoprotein similarly binds and melts its own 98-bp origin but replicates multiple times in a single cell cycle. To examine the actions of this unlicensed viral helicase, we quantitated multimerization of MCV LT molecules as they assembled on MCV DNA origins using real-time single-molecule microscopy. MCV LT formed highly stable double hexamers having 17-fold longer mean lifetime (τ, >1,500 s) on DNA than single hexamers. Unexpectedly, partial MCV LT assembly without double-hexamer formation was sufficient to melt origin dsDNA as measured by RAD51, RPA70, or S1 nuclease cobinding. DNA melting also occurred with truncated MCV LT proteins lacking the helicase domain, but was lost from a protein without the multimerization domain that could bind only as a monomer to DNA. SV40 polyomavirus LT also multimerized to the MCV origin without forming a functional hexamer but still melted origin DNA. MCV origin melting did not require ATP hydrolysis and occurred for both MCV and SV40 LT proteins using the nonhydrolyzable ATP analog, adenylyl-imidodiphosphate (AMP-PNP). LT double hexamers formed in AMP-PNP, and melted DNA, consistent with direct LT hexamer assembly around single-stranded (ss) DNA without the energy-dependent dsDNA-to-ssDNA melting and remodeling steps used by cellular helicases. These results indicate that LT multimerization rather than helicase activity is required for origin DNA melting during unlicensed virus replication.
... The loss of vascular E-selectin expression, an important factor in T-cell entry to the skin, displays significant association with poor intra-tumoral CD8+ infiltration and worsened prognosis of MCC cells [60]. A decreased activity of TILs in MCC signifies the decreased expression of co-stimulatory signal molecules, as well as expression of specific T-cell exhaustion markers [61]. Restriction of T-cell entry into tumor cells and reduction in T-cell function might be considerable and targetable forms of immuno-evasion in MCC [61]. ...
... A decreased activity of TILs in MCC signifies the decreased expression of co-stimulatory signal molecules, as well as expression of specific T-cell exhaustion markers [61]. Restriction of T-cell entry into tumor cells and reduction in T-cell function might be considerable and targetable forms of immuno-evasion in MCC [61]. Besides clonal integration, chronic expression of the two MCPyV oncoproteins also contributes significantly to MCC pathophysiology. ...
Merkel cell carcinoma (MCC) is an uncommon form of skin neoplasm with poor histological differentiation and an aggressive disease process, leading to high recurrence and mortality. There are multiple risk factors in which being in an immunocompromised state is a significant factor, and the discovery of Merkel cell polyomavirus (MCPyV) since 2008 has strengthened causal associations between MCC and immunosuppression. Individuals who have undergone kidney transplantation are therefore more susceptible to having MCC, secondary to post-transplant immunosuppression which plays a vital role in reducing the risk of transplant kidney rejection. Over recent years a rise in the incidence of MCC following kidney transplantation is noted, with increased reporting of such cases. Whilst localized MCC is observed, MCC metastasis to the lymphatic system, brain, bone, liver, lung, and heart has been previously observed in patients with transplanted kidneys. Kidney metastasis is less common and has been only reported in recent years with greater frequency. The management of aggressive, metastatic MCC has historically been palliative, and prognosis is poor. Recently, the use of immune checkpoint inhibitors for metastatic MCC in multi-center phase II clinical trials have shown promising survival outcomes and have been approved for use in countries such as the United States as a first-line treatment. In this review we will explore the potential pathophysiological processes of MCC manifesting post-kidney transplantation. We will then evaluate the epidemiology of MCC within the context of kidney transplantation, before discussing the various clinical presentations, diagnostic measures, surveillance strategies, and current treatment options as well as future directions to best manage MCC in kidney transplant recipients.
... MCC is an immune-sensitive tumor, as highlighted by the association between survival and intra-tumoral levels of cytotoxic CD8+ lymphocytes [27] and of MCPyVspecific T cells [28,29], as well as the identification of specific circulating antibodies that fluctuate along with disease activity [30]. Lymphocytes of the tumor microenvironment exhibit an "exhausted" phenotype with increased expression of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [31] and an increase in CD4+ and CD8+ regulatory T cells (Treg), confirming that loss of immunesurveillance is a key point in the immunoediting process of MCC [31]. ...
... MCC is an immune-sensitive tumor, as highlighted by the association between survival and intra-tumoral levels of cytotoxic CD8+ lymphocytes [27] and of MCPyVspecific T cells [28,29], as well as the identification of specific circulating antibodies that fluctuate along with disease activity [30]. Lymphocytes of the tumor microenvironment exhibit an "exhausted" phenotype with increased expression of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [31] and an increase in CD4+ and CD8+ regulatory T cells (Treg), confirming that loss of immunesurveillance is a key point in the immunoediting process of MCC [31]. ...
Simple Summary
Merkel cell carcinoma (MCC) is a highly aggressive skin cancer and the second cause of skin cancer death after melanoma. MCC is an immunogenic tumor. In recent years, the use of immunotherapy has changed the treatment landscape for patients with metastatic MCC, significantly improving the prognosis. However, the five-year disease-specific survival remains around 64%, underlying the unmet need for novel treatments. This review recapitulates current knowledge about MCC pathogenesis, diagnosis, and management. Emphasis is given to the use of immunotherapy and targeted therapies as well as to future therapeutic perspectives in the neoadjuvant setting and for locally advanced and metastatic MCC.
Abstract
MCC is a rare but highly aggressive skin cancer. The identification of the driving role of Merkel cell polyomavirus (MCPyV) and ultraviolet-induced DNA damage in the oncogenesis of MCC allowed a better understanding of its biological behavior. The presence of MCPyV-specific T cells and lymphocytes exhibiting an ‘exhausted’ phenotype in the tumor microenvironment along with the high prevalence of immunosuppression among affected patients are strong indicators of the immunogenic properties of MCC. The use of immunotherapy has revolutionized the management of patients with advanced MCC with anti-PD-1/PD L1 blockade, providing objective responses in as much as 50–70% of cases when used in first-line treatment. However, acquired resistance or contraindication to immune checkpoint inhibitors can be an issue for a non-negligible number of patients and novel therapeutic strategies are warranted. This review will focus on current management guidelines for MCC and future therapeutic perspectives for advanced disease with an emphasis on molecular pathways, targeted therapies, and immune-based strategies. These new therapies alone or in combination with anti-PD-1/PD-L1 inhibitors could enhance immune responses against tumor cells and overcome acquired resistance to immunotherapy.
... In addition, 50% of the nonactivated T-cells in MCC express PD-1, a marker of T-cell exhaustion. PD-1 interacts with PD-L1, which is often expressed by MCC cells leading to T-cell dysfunction [37,38]. Previous studies have indicated that the density, location, and organization of immune cells within tumors at the time of diagnosis can reflect the host's immune response and help predict the course of tumor progression [39][40][41][42]. ...
... Within most tumors exist TILs, a heterogeneous lymphocyte population composed primarily of T-cells that penetrates the tumor upon the recognition of cancer antigens, therefore potentially contributing to tumor destruction or escape [51]. The prognostic significance of TILs in MCC has been recognized for many years [38,52]. The immunostaining of MCC tumor cryosections has revealed tumor infiltration by various subpopulations of T-cells, including effector, regulatory, and central memory (T CM ) [38] (Figure 2). ...
... The prognostic significance of TILs in MCC has been recognized for many years [38,52]. The immunostaining of MCC tumor cryosections has revealed tumor infiltration by various subpopulations of T-cells, including effector, regulatory, and central memory (T CM ) [38] (Figure 2). MCCs with higher levels of T-cells expressing CLA (cutaneous lymphocyte-associated antigen) demonstrate increased infiltration, while the subset of MCC tumors with T-cells lacking CLA expression fail to penetrate the tumor. ...
Merkel cell carcinoma (MCC) is a rare and frequently lethal skin cancer with neuroendocrine characteristics. MCC can originate from either the presence of MCC polyomavirus (MCPyV) DNA or chronic ultraviolet (UV) exposure that can cause DNA mutations. MCC is predominant in sun-exposed regions of the body and can metastasize to regional lymph nodes, liver, lungs, bone, and brain. Older, light-skinned individuals with a history of significant sun exposure are at the highest risk. Previous studies have shown that tumors containing a high number of tumor-infiltrating T-cells have favorable survival, even in the absence of MCPyV DNA, suggesting that MCPyV infection enhances T-cell infiltration. However, other factors may also play a role in the host antitumor response. Herein, we review the impact of tumor infiltrating lymphocytes (TILs), mainly the CD4+, CD8+, and regulatory T-cell (Tregs) responses on the course of MCC, including their role in initiating MCPyV-specific immune responses. Furthermore, potential research avenues related to T-cell biology in MCC, as well as relevant immunotherapies are discussed.
... Following the then-recent developments linking MCPyV and the immune system to MCC, Bhatia et al. suggested the use of anti-CTLA-4 antibodies such as ipilimumab as potential therapeutic strategies to counteract lymphocytic exhaustion (49). In 2013, several groups reported PD-L1 expression on MCC tumor cells and/or PD-1 expression on TILs in the tumor microenvironment (TME), strengthening the rationale for immunotherapy agents that block the PD-1/PD-L1 axis to be used in MCC treatment (18,50,51). In mid-2015, a phase I study of pembrolizumab included one patient with previouslyuntreated MCC who experienced a DOR of 56+ weeks at time of publication (52). ...
Immuno-oncology is a rapidly evolving field with growing relevance in the treatment of numerous malignancies. The prior study of immunotherapy in dermatologic oncology has largely focused on cutaneous melanoma. However, recent focus has shifted to the use of immunotherapy to treat non-melanoma skin cancers (NMSCs), such as basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC). NMSCs represent the most ubiquitous cancers globally and, while they have a lower propensity to develop into advanced disease than cutaneous melanoma, their absolute mortality burden has recently surpassed that of melanoma. Patients with advanced NMSC are now benefiting from the successes of immunotherapy, including checkpoint inhibition with anti-CTLA-4 and anti-PD-1 monoclonal antibodies. In this review, we discuss the existing clinical evidence for immunotherapy in the treatment of NMSCs, with an emphasis on checkpoint inhibitor therapies. We highlight key studies in the field and provide up-to-date clinical evidence regarding ongoing clinical trials, as well as future study directions. Our review demonstrates that checkpoint inhibitors are positioned to provide unparalleled results in the previously challenging landscape of advanced NMSC treatment.
... Initially described by Cyril Toker in 1972 [3], this cancer metastasizes rapidly and responds relatively poorly to chemotherapy, resulting in low survival rates in its patients [4][5][6][7][8][9][10]. MCCs have also demonstrated the intrinsic ability to resist immunological eradication [6,[11][12][13][14][15]. Though still rare, the incidence of MCC has tripled in the decades following its discovery [16][17][18]. ...
Merkel cell polyomavirus (MCPyV) is a ubiquitous skin infection that can cause Merkel cell carcinoma (MCC), a highly lethal form of skin cancer with a nearly 50% mortality rate. Since the discovery of MCPyV in 2008, great advances have been made to improve our understanding of how the viral encoded oncoproteins contribute to MCC oncogenesis. However, our knowledge of the MCPyV infectious life cycle and its oncogenic mechanisms are still incomplete. The incidence of MCC has tripled over the past two decades, but effective treatments are lacking. Only recently have there been major victories in combatting metastatic MCC with the application of PD-1 immune checkpoint blockade. Still, these immune-based therapies are not ideal for patients with a medical need to maintain systemic immune suppression. As such, a better understanding of MCPyV’s oncogenic mechanisms is needed in order to develop more effective and targeted therapies against virus-associated MCC. In this review, we discuss current areas of interest for MCPyV and MCC research and the progress made in elucidating both the natural host of MCPyV infection and the cell of origin for MCC. We also highlight the remaining gaps in our knowledge on the transcriptional regulation of MCPyV, which may be key to understanding and targeting viral oncogenesis for developing future therapies.
... CD8 + T cells isolated from MCC tumors are capable to kill autologous tumor cells after in-vitro expanding with IL-2/IL-15. (Dowlatshahi et al., 2013). In one study of 38 patients with MCC and 30 healthy donors, both populations had MCPyV-VP1 specific CD8 + T cells. ...
... Overall, MCPyV T-Ag specific T cell response is found in MCPyV + MCC and is associated with tumor burden. Of interest, L-selectin/CCR7 + central memory T cells (TCM) are significantly enhanced in MCPyV + MCC compared to normal skin (Dowlatshahi et al., 2013), although their specificity is not clear. ...
... Increased number of E-selectin-positive vessels in the tumor are associated with greater intratumoral CD8 + lymphocyte infiltration and improved MCC-specific outcome (Afanasiev et al., 2013a). Consistently, it has been reported that a subset of MCC tumors lacks CLA + T cells, which correlate with a lower number of tumor-infiltrating T cells (Dowlatshahi et al., 2013). These data show that disruption of T cell migration into the TME is an evasion strategy for some MCC. ...
Merkel cell carcinoma (MCC) is a rare aggressive skin malignancy that affects predominantly elderly and immunocompromised patients. Merkel cell polyomavirus (MCPyV) is the etiologic agent of 80% MCC, the genome of which is clonally integrated into MCC cells. The genome of MCPyV consists of a circular DNA chain divided by a bidirectional promoter that directs the transcription of the early region (ER) and the late region. The MCPyV ER encodes functional proteins including the small T antigen (sT), the large T antigen (LT), the 57kT, and a protein called alternat frame of the large T open reading frame (ALTO). The sT and LT are crucial for viral replication and exhibit oncogenic potential involved in MCC carcinogenesis, whereas the function of 57kT and ALTO remains elusive. In MCC cells, the sT is expressed in an intact form, while the C-terminal sequence of LT is deleted, giving rise to a truncated form of LT, referred to as trLT or onco-type LT (otLT). The C-terminal truncation removes the helicase domain of LT, preventing viral replication and enhancing its cell growth-promoting effect. The expression of otLT is the hallmark of MCPyV-induced MCC and is pivotal for MCC development. IL-17A is a proinflammatory cytokine with pleiotropic functions essential for the skin and mucous homeostasis. It is specifically crucial for the first-line defense against skin and mucosal pathogens, including fungi, bacteria, as well as viruses, and plays an essential role in tissue repair and remodeling. However, uncontrolled and chronic IL-17A inflammation is deleterious that can lead to inflammatory diseases and cancer. We showed variable IL-17A induction by MCPyV ER-induced proteins. Interestingly, we observed less IL-17A induction by otLT compared to LT. The transition from acute high-level IL-17A to low-grade IL-17A inflammation caused by otLT could be an important event that contributes to MCC development. During infection, the inflammatory response is negatively controlled by multiple mechanisms to avoid pathological inflammation. Autophagy is a conserved degradative process in eukaryotic cells that plays a critical role in material recycling and cellular homeostasis. It is also involved in the regulation of immune response and diseases, such as cancer. We revealed that MCPyV LT enhanced cellular autophagy while otLT did not. Finally, we demonstrated that IL-17A-mediated inflammation increased autophagy. Conversely, autophagy activation inhibits IL-17A-mediated inflammation, suggesting negative feedback of autophagy to prevent over-exuberant inflammation.
