PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody

Abstract

Tumor antigen-targeting monoclonal antibodies (TA-targeting mAbs) are used as therapeutics in many malignancies and their capacity to mobilize the host immunity puts them at the forefront of anti-cancer immunotherapies. Both innate and adaptive immune cells have been associated with the therapeutic activity of such antibodies, but tumor escape from mAb-induced tumor immune surveillance remains one of the main clinical issues. In this preclinical study, we grafted immunocompetent and immunocompromised mice with the B16F10 mouse melanoma cell line and treated them with the TA99 TA-targeting mAb to analyze the immune mechanisms associated with the tumor response and resistance to TA99 monotherapy. In immunocompetent mice TA99 treatment strongly increased the fraction of CD8 and CD4 effector T cells in the tumor compared with isotype control, highlighting the specific immune modulation of the tumor microenvironment by TA99. However, in most mice, TA99 immunotherapy could not prevent immune effector exhaustion and the recruitment of regulatory CD4 T cells and consequently tumor escape from immune surveillance. Remarkably, anti-PD-1 treatment at the time of tumor emergence restored the Th1 effector functions of CD4 and CD8 T cells as well as of natural killer and γδT cells, which translated into a significant slow-down of tumor progression and extended survival. Our findings provide the first evidence that PD-1 blockade at the time of tumor emergence can efficiently boost the host anti-tumor immune response initiated several weeks before by the TA-targeting mAb. These results are promising for the design of combined therapies to sensitize non-responder or resistant patients.

A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth

“…In fact, TRIMELVax/anti-PD-1 combination generated only marginal enhancing of TRIMELVax efficiency, although long-term effects in tumor-bearing animals cannot be discarded. In our model, treatment of tumor-bearing mice with anti-PD-1 alone induced tumor growth retardation, but did not have a significant impact on the overall survival, in line with other observations, 40 41 which can be explained by acquired resistance to anti-PD-1/PDL1 therapies described in both mouse models and clinical trials. 3 42 43 …”

Novel Immunotherapeutic Approaches for Neuroblastoma and Malignant Melanoma

“…They demonstrated that anti-PD-1 treatment of mice, at the time of tumor emergence, restored the effector functions of T cells, NK cells, and γδ T cells, leading to the inhibition of tumor progression and extension of survival. These data confirmed that combination of checkpoint blockade and immunotherapy may represent a promising approach for melanoma patients [ 81 ].…”

FTO-mediated cytoplasmic m6Amdemethylation adjusts stem-like properties in colorectal cancer cell

“…Three-µm thin sections of formalin-fixed paraffin-embedded tissues were mounted on Flex microscope slides (Dako) and allowed to dry overnight at room temperature before immunohistochemistry processing, as previously described [63]. Briefly, PT-Link ® system (Dako) was used for pre-treatment.…”