Lymphatic PD-L1 Expression Restricts Tumor-Specific CD8+ T-cell Responses.

Lymph node (LN)-resident lymphatic endothelial cells (LEC) mediate peripheral tolerance by self-antigen presentation on MHC-I and constitutive expression of T-cell inhibitory molecules, including PD-L1 (CD274). Tumor-associated LECs also upregulate PD-L1, but the specific role of lymphatic PD-L1 in tumor immunity is not well understood. In this study, we generated a mouse model lacking lymphatic PD-L1 expression and challenged these mice with two orthotopic tumor models, B16F10 melanoma and MC38 colorectal carcinoma. Lymphatic PD-L1 deficiency resulted in consistent expansion of tumor-specific CD8+ T cells in tumor-draining LNs in both tumor models, reduced primary tumor growth in the MC38 model, and increased efficacy of adoptive T-cell therapy in the B16F10 model. Strikingly, lymphatic PD-L1 acted primarily by inducing apoptosis in tumor-specific CD8+ central memory T cells. Overall, these findings demonstrate that LECs restrain tumor-specific immunity via PD-L1, which may explain why some patients with cancer without PD-L1 expression in the tumor microenvironment still respond to PD-L1/PD-1-targeted immunotherapy. SIGNIFICANCE: A new lymphatic-specific PD-L1 knockout mouse model reveals that lymphatic endothelial PD-L1 expression reduces tumor immunity, inducing apoptosis in tumor-specific CD8+ central memory cells in tumor-draining lymph nodes.

The targeted delivery of interleukin-12 to the carcinoembryonic antigen increases the intratumoral density of NK and CD8+ T cell in an immunocompetent mouse model of colorectal cancer.

The recent success achieved by immune checkpoint inhibitors in the field of immuno-oncology has been less evident for the treatment of metastatic colorectal cancer (mCRC) patients. To date, cancer immunotherapy has been efficacious only in few patients bearing high mutational burden (less than 25%) mCRCs. In this Communication, we report the generation of a novel antibody cytokine fusion protein (termed Sm3E-mIL12) targeting the CRC-associated carcinoembryonic antigen (CEA). The antibody moiety bound avidly to CEA when immobilized on solid supports, and selectively stained C51 tumor cells transfected with the antigen (C51-CEA). The cytokine payload retained full activity in vitro, as compared to the parental recombinant interleukin-12 (IL12). Ex vivo microscopic analyses revealed a homogenous distribution of Sm3E-mIL12 in the neoplastic mass upon intravenous administration. In vivo, Sm3E-mIL12 was well tolerated up to 180 µg per mouse. The targeted delivery of IL12 to CEA-expressing C51 carcinomas led to durable complete responses in 60% of the treated mice. The intratumoral density of immune effector cells was markedly increased after the third injection of Sm3E-mIL12, in keeping with the progressive regression of the neoplastic mass. The data suggest that a fully human analogue may be considered for the treatment of patients with mCRC.