CDKN2A Deletion in Melanoma Excludes T Cell Infiltration by Repressing Chemokine Expression in a Cell Cycle-Dependent Manner

Abstract

T-cell-mediated immune response is the prerequisite for T-cell-based immunotherapy. However, the limitation of T-cell infiltration in solid tumors restricted the therapeutic effect of T-cell-based immunotherapy. The present study screened the molecular and genetic features of The Cancer Genome Atlas (TCGA)-skin cutaneous melanoma (SKCM) cohort, revealing that T-cell infiltration negatively correlated with genome copy number alteration. The analysis of the TCGA-SKCM cohort indicated that the copy number of CDKN2A was significantly decreased in patients with low T-cell infiltration. The results were validated in the other two melanoma cohorts (DFCI, Science 2015, and TGEN, Genome Res 2017). Besides, the immunohistochemistry analysis of CDKN2A and CD8 expression in 5 melanoma in situ and 15 invasive melanoma patients also showed that CD8 expression was decreased in the patients with low CDKN2A expression and there was a positive correlation between CDKN2A and CD8 expression in these patients. Interestingly, the CDKN2A deletion group and the group with low expression of T-cell markers shared similar gene and pathway alteration as compared with the normal CDKN2A group and the group with high expression of T-cell markers, especially the chemokine pathway. Further mechanistic study indicated that CDKN2A enhanced T cell recruitment and chemokine expression possibly through modulating MAPK and NF-κB signaling pathways in a cell cycle–dependent manner. Finally, we also found that CDKN2A deletion negatively correlated with the expression of T-cell markers in many other cancer types. In conclusion, CDKN2A deletion could inhibit T cell infiltration by inhibiting chemokine expression in a cell cycle dependent manner.

CDKN2A is a prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma

“…The high expression of CDKN2A can promote the proliferation of cancer cells, inhibit the apoptosis of cancer cells, induce tumor interstitial angiogenesis, reduce the sensitivity of cancer cells to chemoradiotherapy, and ultimately affect the prognosis of HCC patients [ 35 ]. Recently, it has been reported that CDKN2A deletion can inhibit T-cell infiltration by inhibiting the expression of chemokines in a cell cycle dependent manner [ 36 ]. Although the specific molecular mechanism of CDKN2A regulation is still unclear, which may be related to p53 protein, CDKN2A is expected to become a target of HCC treatment in view of its important role in the occurrence and development of HCC.…”

It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy

“…Among challenges faced by the future of cancer immunotherapy, is understanding cancer-intrinsic factors regulating TME leading to immune evasion (Wellenstein and de Visser, 2018;Hegde and Chen, 2020). Recent studies found that genomic CDKN2A loss-of-function is associated with worse clinical outcome in patients treated with cancer immunotherapy in multiple cancer types (Adib et al, 2021;Gutiontov et al, 2021;Zhu et al, 2021). The reduced benefit of cancer immunotherapy can be attributed to altered tumorimmune microenvironment and compromised immune cell functions.…”

Identification and validation of Birc5 as a novel activated cell cycle program biomarker associated with infiltration of immunosuppressive myeloid‐derived suppressor cells in hepatocellular carcinoma

“…Currently, increasing evidence has revealed that genes related to cell cycle program are capable of remodeling tumor microenvironment (TME) and can regulate tumor immune responses, underscoring the potential strategies of targeting cell cycle‐associated genes for immunotherapy of human cancers 12,13 . For instance, inhibiting the expression of CDKN2A , a member of cyclin‐dependent kinase (CDK) inhibitors, could lead to invasion, progression, and immunotherapy resistance in melanoma 14–16 . CDKN2A deletion repressed T‐cell infiltration by suppressing chemokine expression in a cell cycle‐dependent manner and might account for immunotherapy failure 15 .…”

“… 12 , 13 For instance, inhibiting the expression of CDKN2A , a member of cyclin‐dependent kinase (CDK) inhibitors, could lead to invasion, progression, and immunotherapy resistance in melanoma. 14 , 15 , 16 CDKN2A deletion repressed T‐cell infiltration by suppressing chemokine expression in a cell cycle‐dependent manner and might account for immunotherapy failure. 15 Besides, TP53 , associated with STK11 and EGFR , has been proved to be a major determinant of tumor immune profile.…”

“… 14 , 15 , 16 CDKN2A deletion repressed T‐cell infiltration by suppressing chemokine expression in a cell cycle‐dependent manner and might account for immunotherapy failure. 15 Besides, TP53 , associated with STK11 and EGFR , has been proved to be a major determinant of tumor immune profile. Previous research showed that patients with TP53 mutation and without alteration in STK11 and EGFR had the highest levels of CD8 + T‐cell and PD‐L1 expression and exhibited best responses to PD‐1 blockade.…”