Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition

Abstract

Background Immune checkpoint inhibitors (ICIs) for solid tumors, including those targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have shown impressive clinical efficacy, however, most patients do not achieve durable responses. One major therapeutic obstacle is the immunosuppressive tumor immune microenvironment (TIME). Thus, we hypothesized that a strategy combining tumor-directed radiation with TIME immunomodulation could improve ICI response rates in established solid tumors. Methods Using a syngeneic mouse model of human papillomavirus (HPV)-associated head and neck cancer, mEER, we developed a maximally effective regimen combining PD-1 and CTLA-4 inhibition, tumor-directed radiation, and two existing immunomodulatory drugs: cyclophosphamide (CTX) and a small-molecule inducible nitric oxide synthase (iNOS) inhibitor, L-n6-(1-iminoethyl)-lysine (L-NIL). We compared the effects of the various combinations of this regimen on tumor growth, overall survival, establishment of immunologic memory, and immunologic changes with flow cytometry and quantitative multiplex immunofluorescence. Results We found PD-1 and CTLA-4 blockade, and radiotherapy alone or in combination, incapable of clearing established tumors or reversing the unfavorable balance of effector to suppressor cells in the TIME. However, modulation of the TIME with cyclophosphamide (CTX) and L-NIL in combination with dual checkpoint inhibition and radiation led to rejection of over 70% of established mEER tumors and doubled median survival in the B16 melanoma model. Anti-tumor activity was CD8 + T cell-dependent and led to development of immunologic memory against tumor-associated HPV antigens. Immune profiling revealed that CTX/L-NIL induced remodeling of myeloid cell populations in the TIME and tumor-draining lymph node and drove subsequent activation and intratumoral infiltration of CD8 + effector T cells. Conclusions Overall, this study demonstrates that modulation of the immunosuppressive TIME is required to unlock the benefits of ICIs and radiotherapy to induce immunologic rejection of treatment-refractory established solid tumors. Electronic supplementary material The online version of this article (10.1186/s40425-019-0698-6) contains supplementary material, which is available to authorized users.

Immunobiology of Uveal Melanoma: State of the Art and Therapeutic Targets

“…As a matter of fact, expression of iNOS has been shown to represent a negative prognostic factors for multiple types of cancer, including primary UM (94, 95). In particular, recent evidence seems to indicate that NO may act as an addition local immune checkpoint inhibitor, favoring immune evasion of the tumor, by modulation of the acquisition of stem cell-like capacities, the metabolic reprogramming of tumor-infiltrating immune cells, and the induction of myeloid-derived suppressor cells that deplete arginine, via the iNOS pathway, and consequently inhibit T cell function (96, 97).…”

Implementation of the Chick Chorioallantoic Membrane (CAM) Model in Radiation Biology and Experimental Radiation Oncology Research

“…Although the first observations about a potential contribution of the host immune system to successful tumor eradication by the local application of ionizing radiation date more than 100 years ago (for review see: [76]), clinical observations about radiation-induced eradication of tumor lesions outside the radiation field (abscopal effects) remained rare [77]. The progress in immunotherapy and the seminal discoveries that radiotherapy can overcome immunosuppressive barriers in the tumor microenvironment, induce immunogenic alterations in tumor cells, and even elicit local and systemic T-cell-mediated antitumor immune responses expedited interest in exploiting the benefit of combining radiotherapy with immunotherapy [30,31,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91]. This knowledge is now being increasingly used in the design of new treatment strategies, e.g., by combining RT with immunotherapy [84,92,93,94].…”

Consolidation treatment of durvalumab after chemoradiation in real‐world patients with stage III unresectable non‐small cell lung cancer

“…Previous studies have reported that chemoradiation can give rise to a number of immune reactions crucial to tumor containment. These include increased type I interferon and major histocompatibility complex (MHC) class I expression, as well as enhanced priming capacity of tumor‐infiltrating dendritic cells; all of which may contribute to the increased tumor infiltration of the effector CD8 T cells . Given that, the subsequent administration of the programmed cell death 1 (PD‐1) or PD‐1 ligand (PD‐L1) inhibitors, acting to mitigate the PD‐1/PD‐L1‐mediated immunosuppression, sustains the effector immunity established post‐chemoradiation around the tumor microenvironment and thereby contain the residual disease through an operational immune surveillance.…”