A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy

Abstract

Immune checkpoint inhibitors have shown great potential in treating solid tumors, inducing durable remission and prolonged survival time in responders. Despite their promise, a large fraction of patients remains unresponsive to these treatments highlighting the need for biomarkers that can predict patient sensitivity. Pre-treatment gene expression profiles for patients receiving immune checkpoint inhibitors have recently become available, establishing a new medium by which to discover biomarkers that predict therapy response. In this study, we mined for transcriptomic correlates of response by applying immune cell-derived gene expression signatures to publicly available datasets containing matched gene expression and response efficacy information. These datasets were comprised of urothelial carcinoma patients receiving anti-PD-L1 (n = 25), melanoma patients receiving anti-PD-1 (n = 28), and melanoma patients receiving anti-CTLA-4 (n = 42). We identified one signature, derived from a subpopulation of B cells, with scores that were significantly and reproducibly elevated in patients experiencing clinical benefit following therapy targeting the PD-1/PD-L1 axis and were additionally elevated in patients responsive to anti-CTLA-4 therapy. Multivariate models revealed that this signature was associated with response independent of other response-predictive biomarkers, including tumor mutation burden. Functional annotation of the signature revealed it to be associated with features indicative of an immunologically active microenvironment, including B and T cell activation as well as antigen presentation activity. The preliminary findings presented detail a transcriptomic signature associated with response to multiple checkpoint inhibitors and suggest novel biological associations that warrant further investigation.

The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies

“…An increased presence of plasmablasts had previously been described in the blood of melanoma, lung, and renal cell carcinomas patients responding to anti-CTLA-4 and anti-PD-1 therapies (56). A gene signature related to memory B cells (111) was reported to be associated with clinical benefit and improved survival in anti-PD-1-and anti-CTLA-4-treated melanoma patients and in anti-PD-L1-treated urothelial carcinoma (112). B-cell-secreted antibodies have also been related to ICB response.…”

The role of B lymphocytes in the immuno-biology of non-small-cell lung cancer

“…This is particularly the case given earlier data showing that clinical benefit with ipilimumab was greater in melanoma patients with sero-positivity against NY-ESO [89]: as mentioned above, the CTags appear to be potent immunogens stimulating antibody responses. Furthermore, gene-expression profiling in urothelial carcinoma and melanoma patients undergoing both anti-PD-1/PD-L1 and anti-CTLA4 therapy identified a memory B-cell (MBL) signature which was significantly and reproducibly elevated in patients showing clinical benefit [90]. It significantly outperformed other immune cell signatures and remained significantly associated with outcome when including tumour mutational burden, copy number aberration burden and checkpoint expression.…”

The Risks and Benefits of Immune Checkpoint Blockade in Anti-AChR Antibody-Seropositive Non-Small Cell Lung Cancer Patients

“…Understanding the complex tumor microenvironment offers the opportunity to make better prognostic evaluations and select optimum treatments [26,27,30]. Accumulating evidence suggests that a high density of tumor-infiltrating CD8+ T cells and CD20+ B cells strongly associates with positive clinical outcomes in various cancer types [20,21,22,31]. However, the immune contexture of anti-AChR Ab-seropositive tumor response to immune checkpoint inhibitors without developing MG remains unknown.…”