Resistance to checkpoint blockade therapy through inactivation of antigen presentation

Abstract

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

“…Among the cancer‐related markers, we observed the expression of β2M, STAT3, STING, and β‐catenin (Figure B). The expression of β2M suggests that tumour antigens are presented via HLA‐A in these tumour areas, thus supporting the efficacy of ICI . Total levels of STAT3 were elevated, but not in its activated phosphorylated form (pY705), which regulates gene transcription for modulation of immunosuppressive factors .…”

High‐dose glucocorticoids for the treatment of ipilimumab‐induced hypophysitis is associated with reduced survival in patients with melanoma

“…12,13,27 Mutations in JAK1 and JAK2 and defects in INF-c signaling have been implicated in resistance to anti-CTLA-4 and anti-PD-1 therapy. 10 Glucocorticoids extensively modify cytokine signaling and can inhibit the interleukin-2 and INF-c pathways. 28 Mutations in b-2 microglobulin also appear to impart resistance to treatment with CTLA-4 and PD-1 antibodies.…”

“…[6][7][8] Optimal management strategies for patients with primary hypophysitis and checkpoint inhibitor (CPI)-associated hypophysitis are poorly defined; therefore, treatment patterns, including glucocorticoid dosages, vary. [10][11][12] High doses of glucocorticoids inhibit the immune response, including some pathways linked to CPI resistance. 9 Defects in the immune response are associated with primary and acquired resistance to CPIs.…”

OMIC signatures to understand cancer immunosurveillance and immunoediting: Melanoma and immune cells interplay in immunotherapy

“…This group found β2‐microglobulin gene mutations and loss of heterozygosity (LOH) at baseline in a cohort of melanoma samples taken from patients with intrinsic resistance to anti‐CTLA‐4 and anti‐PD‐1 therapy . β2‐microglobulin mutations have commonly been observed enriched in patients with disease relapse . Other study found enriched cellular ( FYB , CXCL9, CD69, CD8A, CARD11 , and CD5 ) and humoral (immunoglobulin heavy chain variants) immune responses in the group with clinical benefit to ipilimumab therapy …”