Prognostic value of B cells in cutaneous melanoma

Abstract

Background Measures of the adaptive immune response have prognostic and predictive associations in melanoma and other cancer types. Specifically, intratumoral T cell density and function have considerable prognostic and predictive value in skin cutaneous melanoma (SKCM). Less is known about the significance of tumor-infiltrating B cells in SKCM. Our goal was to understand the prognostic and predictive value of B cell phenotypic subsets in SKCM using RNA sequencing. Methods We used our previously published algorithm, V’DJer, to assemble B cell receptor (BCR) repertoires and estimate diversity from short-read RNA sequencing (RNA-seq). We applied machine learning-based cellular phenotype classifiers to measure relative similarity of bulk tumor sample gene expression profiles and different B cell phenotypes. We assessed these aspects of B cell biology in 473 SKCM from the Cancer Genome Atlas Project (TCGA) as well as in RNA-seq data corresponding to tumor samples procured from patients who received CTLA-4 and PD-1 inhibitors for metastatic SKCM. Results We found that the BCR repertoire was associated with different clinical factors, such as tumor tissue site and sex. However, increased clonality of the BCR repertoire was favorably prognostic in SKCM and was prognostic even after first conditioning on various clinical factors. Mutation burden was not correlated with any BCR measurement, and no specific mutation had an altered BCR repertoire. Lack of an assembled BCR in pre-treatment tumor tissues was associated with a lack of anti-tumor response to a CTLA-4 inhibitor in metastatic SKCM. Conclusions These findings suggest an important prognostic and predictive role for B cell characteristics in SKCM. This has implications for melanoma immunobiology and potential development of immunogenomics features to predict survival and response to immunotherapy. Electronic supplementary material The online version of this article (10.1186/s13073-019-0647-5) contains supplementary material, which is available to authorized users.

B cells and tertiary lymphoid structures promote immunotherapy response

“…In this regard, the benefit of a high CD8 + T-cell density within a tumor is abrogated in the absence of TLSassociated DCs 28 . Mature TLS exhibit evidence for germinal center formation 29,30 , and oligoclonal B-cell responses have been identified in cutaneous melanoma and metastases 31,32 , further suggesting an active humoral anti-tumor response within the TLS and one driven by Bcells. Notably, the role of B-cells and, in particular, TLS in response to ICB remains unclear.…”

Distinct Genomic Features Across Cytolytic Subgroups in Skin Melanoma

“…Additionally, CD8 + T-cell in ltration associates with a better response of cancer patients to chemotherapy [101], neoadjuvant therapy [102] and anti-PD-1 immunotherapy [103]. A key role for tumor-in ltrating B cells in modulating the anti-tumor immune response, was recently proposed in skin melanoma [104]. B cells play an important prognostic role and can predict non-response to an immune checkpoint inhibitor in metastatic melanoma [104].…”

“…A key role for tumor-in ltrating B cells in modulating the anti-tumor immune response, was recently proposed in skin melanoma [104]. B cells play an important prognostic role and can predict non-response to an immune checkpoint inhibitor in metastatic melanoma [104]. The enrichment of CYT-high tumors in M1 macrophages is in line with their suppressive role in cancer progression, while that of M2 macrophages in CYT-low tumors, underscores their role in favoring tumor growth and dissemination [105].…”

Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting

“…When the expression levels of BCR are low, there is an option to increase the sensitivity of the algorithm at the cost of increasing the demand for computational resources. V'DJer has been used, for example, to retrieve antibodies from RNA sequencing data of melanoma patients from TCGA repository [131,132]. At present, TCGA contains expression analyses of 87 MPM patients (TCGA-MESO) that could be used for this purpose.…”