Tumor CD155 Expression Is Associated with Resistance to Anti-PD1 Immunotherapy in Metastatic Melanoma

Abstract

Resistance to anti-PD1-based immune checkpoint blockade (ICB) remains a problem for the treatment of metastatic melanoma. Tumor cells as well as host myeloid cells can express the immune checkpoint ligand CD155 to regulate immune cell function. However, the effect of tumor CD155 on the immune context of human melanoma has not been well described. This observational study characterizes tumor CD155 ligand expression by metastatic melanoma tumors and correlates results with differences in immune cell features and response to ICB.Experimental Design: Pretreatment tumor specimens, from 155 patients with metastatic melanoma treated with ICB and from 50 patients treated with BRAF/MEK-directed targeted therapy, were assessed for CD155 expression by IHC. Intratumor T-cell features were analyzed using multiplex-immunohistofluorescence for CD8, PD1, and SOX10. Correlations were made between CD155 tumor level and bulk tumor RNA sequencing results, as well as clinical RECIST response and progression-free survival.Results: High pretreatment CD155 tumor levels correlated with high parenchymal PD1 þ CD8 þ /CD8 þ T-cell ratios (PD1 tR ) and poor response to anti-PD1 therapy. In PDL1 negative tumors, high CD155 tumor expression was associated with patients who had poor response to combination anti-PD1/ CTLA4 therapy.Conclusions: Our findings are the first to suggest that tumor CD155 supports an increase in the fraction of PD1 þ CD8 þ T cells in anti-PD1 refractory melanoma tumors and, further, that targeting the CD155 pathway might improve response to anti-PD1 therapy for patients with metastatic melanoma.

Impact of immune checkpoint gene CD155 Ala67Thr and CD226 Gly307Ser polymorphisms on small cell lung cancer clinical outcome

“…In this study, polymorphisms in the CD155 and CD226 was associated with survival outcomes in SCLC patients who received chemotherapy. CD155 and CD226 are one of targets in immuno-oncology 43,44 . Therefore, variants in CD155 and CD226 may have a greater impact on clinical outcomes with immunotherapy alone or in combination with chemotherapy than with chemotherapy alone.…”

TIGIT in cancer immunotherapy

“…In addition, tumor CD155 expression is associated with increased tumor-infiltrating PD-1 + CD8 + T cells and resistance to anti-PD-1 immunotherapy in metastatic melanoma. 44 Collectively, these findings suggest that targeting the CD155 pathway with combinatorial ICB (TIGIT and CD96) may improve response to PD-1 blockade.…”

Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma

“…7 8 Intratumoral delivery of the oncolytic poliovirus PVSRIPO, the live attenuated, type I poliovirus (Sabin) vaccine carrying an internal ribosomal entry site (IRES) of human rhinovirus type 2, 9 has shown initial promise in patients with recurrent glioblastoma multiforme. 10 PVSRIPO enters cells via the poliovirus receptor CD155, which is widely expressed on neoplastic cells in many solid cancers, 11 including melanoma, 12 as well as on all antigen-presenting cells (APCs) of monocytic lineage. 13 Accordingly, PVSRIPO elicits cytopathogenic damage and host Open access innate type I/III interferon (IFN) responses in cancer cells 14 and activates tumor-associated APC in the TME in preclinical models.…”