Abstract 941: B cells are required to generate optimal antitumor immunity in response to PD-1 blockade treatment
Authors: Singh Shubhra , Bavisi Karishma , Roszik Jason , Diab Adi , Davis Richard E. , Hwu Patrick , Overwijk Willem W. , Singh Manisha 
Published: August 2019

Background: Melanoma is the most deadly form of skin cancer. Although, the immunogenic nature of melanoma makes this disease susceptible to immunotherapy, metastatic melanoma remains highly resistant to established immunotherapies like cancer vaccines. Anti-PD-1 antibodies alone showed great clinical activity but were still ineffective in many melanoma patients. These reports highlight the need to understand the molecular mechanism of immunotherapy induced anti-melanoma immune responses to develop new approaches for effective therapy against melanoma. B cells augment CD8+ T cell-mediated immunity during autoimmunity and allograft rejection, but the role of B cells in anti-tumor CD8+ T cell immunity and in cancer patient survival is controversial. Recently, we reported that intratumoral stimulation of TLR-7/8 in a mouse model of melanoma induced tumor regression and activation of B cells. B cells were required for tumor suppression in an antibody-independent manner. Also, we found that melanoma patients who responded to anti-PD-1 blockade therapy had significantly more B cells and CD8+ T cells in tumors than non-responders. Based on these evidences, we hypothesized that activated B cells induce and/or enhance anti-melanoma CD8+ T cell immunity in response to immunotherapy.

Methods: B16 melanoma mouse model was used. Wild type and B cell Knockout mice were used to determine treatment efficacy and generation of tumor-specific CD8+T cells in response to PD-L1 blockade and/or TLR-7/8 activation. TLR-7/8 agonist activated B cells were isolated and adoptively transferred into tumor-bearing B cell KO mice, which were treated with anti-PD-L1.Therapeutic efficacy and melanoma-specific CD8+ T cell immunity were determined.

Results: We found that absence of B cells not only decreases the efficacy of TLR-7/8 agonist or anti-PDL-1 abs monotherapy but also TLR-7/8 agonist and anti-PD-L1 abs combination therapy. In addition, mice were unable to develop potent anti- melanoma CD8+T cell immunity in the absence of B cells in response to either mono or combination therapy. Interestingly, we reported prolonged survival of tumor bearing B cell KO mice which received TLR-7/8 agonist activated B cells compared to inactivated B cells recipients in response to anti-PD-L1 antibody therapy.

Conclusions: These results suggest that activated B cells enhance anti-melanoma CD8+ T cell immunity in response to immunotherapy. We expect our findings to lead the field closer to development of biomarkers based on B cell activation that predict response to immunotherapy. Our findings may also facilitate design of more effective anti-melanoma immunotherapy.

Citation Format: Shubhra Singh, Karishma Bavisi, Jason Roszik, Adi Diab, Richard E. Davis, Patrick Hwu, Willem W. Overwijk, Manisha Singh. B cells are required to generate optimal antitumor immunity in response to PD-1 blockade treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 941.