Lack of myeloid cell infiltration as an acquired resistance strategy to immunotherapy

Abstract

BackgroundImmunotherapy of cancer is successful but tumor regression often is incomplete and followed by escape. Understanding the mechanisms underlying this acquired resistance will aid the development of more effective treatments.MethodsWe exploited a mouse model where tumor-specific therapeutic vaccination results in tumor regression, followed by local recurrence and resistance. In depth studies on systemic, local and tumor intrinsic changes were performed with flow and mass cytometry, immunohistochemistry, transcriptomics and several perturbation studies with inhibitors or agonistic antibodies in mice. Main findings were recapitulated in vaccinated patients.ResultsFull tumor regression and cure of tumor-bearing mice is dependent on the magnitude of the vaccine-induced T-cell response. Recurrence of tumors did not involve classical immune escape mechanisms, such as antigen-presentation alterations, immune checkpoint expression, resistance to killing or local immune suppression. However, the recurrent tumors displayed a changed transcriptome with alterations in p53, tumor necrosis factor-α and transforming growth factor-β signaling pathways and they became immunologically cold. Remarkably, ex vivo cell-sorted recurrent tumors, directly reinjected in naïve hosts retained their resistance to vaccination despite a strong infiltration with tumor-specific CD8+ T cells, similar to that of vaccine-responsive tumors. The influx of inflammatory mature myeloid effector cells in the resistant tumors, however, was impaired and this turned out to be the underlying mechanisms as restoration of inflammatory myeloid cell infiltration reinstated the sensitivity of these refractory tumors to vaccination. Notably, impaired myeloid cell infiltration after vaccination was also associated with vaccine resistance in patients.ConclusionAn immunotherapy-induced disability of tumor cells to attract innate myeloid effector cells formed a major mechanism underlying immune escape and acquired resistance. These data not only stresses the importance of myeloid effector cells during immunotherapy but also demands for new studies to harness their tumoricidal activities.

IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors

“…33 Therapy failure due to an inadequate intratumoral macrophage response, despite the presence of fully activated intratumoral tumor-specific CD8 + T cells, fits with earlier reports demonstrating that macrophages are required for TC-1 tumor regression after therapeutic vaccination 14 26 and functions as a secondary immune escape mechanism. 34 Notably, while these effects were most prominently demonstrated in the context of high levels of tumor-produced IL-6, similar observations were made in the TC-1 control tumor model, which produced much lower levels of IL-6. We previously showed that IL-6 production by tumors altered the function of spontaneously tumor-infiltrating DCs and macrophages, reflected by a lower expression of MHC class II by these myeloid cell subsets.…”

Combining Photodynamic Therapy with Immunostimulatory Nanoparticles Elicits Effective Anti-Tumor Immune Responses in Preclinical Murine Models

“…Interestingly, NPs also induced the infiltration of neutrophils in the untreated tumor ( Supplementary Materials Figure S6A ). The levels of mature (CD86 + ) and inflammatory (Ly6C high ) myeloid cells have recently been shown to increase in treatment-responsive tumors but not in relapsed tumors that display resistance to treatment [ 62 ]. In line with this, we observed an increase in the levels of mature inflammatory myeloid cells and a decrease in non-inflammatory (Ly6C − ) cells in the treated tumor after treatment with the combination, compared to all other treatments ( Figure 6 A).…”

Dual Role of p73 in Cancer Microenvironment and DNA Damage Response

“…Tumour microenvironment is determined by crosstalk between different signalling pathways taking place in cancer cells, immune cells, and other cancer-associated cells such as fibroblasts [ 96 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ].…”