Predictors of responses to immune checkpoint blockade in advanced melanoma

Abstract

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.

The COX2 Effector Microsomal PGE2 Synthase 1 is a Regulator of Immunosuppression in Cutaneous Melanoma

“…The understanding of mechanisms and resultant improvements for immunotherapies of melanoma continue to emerge, resulting in progress toward reducing the overall lethality of melanoma (1)(2)(3)(4). Although many immunotherapies produce an initial response, most advanced melanomas (and other late-stage cancers) develop resistance; because this often leads to relapse, there is an urgent need to identify and counteract the mechanisms responsible.…”

Deep analysis of the USP18-dependent ISGylome and proteome unveils important roles for USP18 in tumour cell antigenicity and radiosensitivity

“…Interestingly, PD-L1 levels, a prognostic factor for ICB therapy when using PD1 inhibitors, were also higher in USP18 KO as compared to WT cells, and PD-L1 was also upregulated on the T cells following interaction with these cells. This is noteworthy as other studies have linked the expression of PD-L1 on CD8 + and CD4 + T cells with patient response to ICB, suggesting PD-L1 expression in CD8 + T cells as a prognostic marker in melanoma 12,63,64 . As the innate immune response is activated by radiotherapy 13,15,16 and ADAR recently described as an important factor in resistance to RT 7 , we decided to perform a second round of functional experiments consisting of irradiating our cancer cells and evaluating viability and clonogenicity after RT.…”

“…However, its expression on T cells has been mostly linked to inhibition of their responses 61,62 . Other studies indicates that expression of PD-L1 on CD8 + and CD4 + T cells correlates with patient response to ICB, suggesting PD-L1 expression in CD8 + T cells as a prognostic marker in melanoma 12,63,64 .…”

“…Many patients develop resistance 1 to treatment; Moreover, ICB frequently has profound side effects, calling for the discovery of predictive biomarkers of ICB success and for novel ways to boost ICB therapy further. Numerous studies point towards defects in interferon-dependent pattern recognition pathways [2][3][4][5][6][7][8] and the antigen-presentation pathway 9,10 as the main resistance mechanisms tumour cells use to avoid the immune system and to escape the effects of immunotherapy 11,12 . In addition to the roles of elements of the innate immune response in modulating the efficacy of cancer immunotherapy, it has also been reported that radiotherapy promotes the expression of interferon-stimulated genes (ISGs) that are involved in resistance to ionizing irradiation 5,[13][14][15][16] .…”

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

“…Given this key role, IFNs have been implicated in primary and acquired resistance to ICBs [47][48][49]. Accordingly, PD-L1, either constitutively expressed or induced by IFNs, is considered a predictive biomarker of response to ICBs [38,50]. However, the identification of additional reliable biomarkers to select patients who are more likely to respond to ICBs is urgently needed.…”