Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy

Abstract

BackgroundChemoradiotherapy (CRT) remains one of the most common cancer treatment modalities, and recent data suggest that CRT is maximally effective when there is generation of an anti-tumoral immune response. However, CRT has also been shown to promote immunosuppressive mechanisms which must be blocked or reversed to maximize its immune stimulating effects.MethodsTherefore, using a preclinical model of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), we developed a clinically relevant therapy combining CRT and two existing immunomodulatory drugs: cyclophosphamide (CTX) and the small molecule inducible nitric oxide synthase (iNOS) inhibitor L-n6-(1-iminoethyl)-lysine (L-NIL). In this model, we treated the syngeneic HPV-HNSCC mEER tumor-bearing mice with fractionated (10 fractions of 3 Gy) tumor-directed radiation and weekly cisplatin administration. We compared the immune responses induced by CRT and those induced by combinatory treatment (CRT + CTX/L-NIL) with flow cytometry, quantitative multiplex immunofluorescence and by profiling immune-related gene expression changes.ResultsWe show that combination treatment favorably remodels the tumor myeloid immune microenvironment including an increase in anti-tumor immune cell types (inflammatory monocytes and M1-like macrophages) and a decrease in immunosuppressive granulocytic myeloid-derived suppressor cells (MDSCs). Intratumoral T cell infiltration and tumor antigen specificity of T cells were also improved, including a 31.8-fold increase in the CD8+ T cell/ regulatory T cell ratio and a significant increase in tumor antigen-specific CD8+ T cells compared to CRT alone. CTX/LNIL immunomodulation was also shown to significantly improve CRT efficacy, leading to rejection of 21% established tumors in a CD8-dependent manner.ConclusionsOverall, these data show that modulation of the tumor immune microenvironment with CTX/L-NIL enhances susceptibility of treatment-refractory tumors to CRT. The combination of tumor immune microenvironment modulation with CRT constitutes a translationally relevant approach to enhance CRT efficacy through enhanced immune activation.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0485-9) contains supplementary material, which is available to authorized users.

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

“…Various molecules, including IL-15, CD96, CD47, and CD137 have potential inhibitory effects. We also summarize receptor-mediated and combination therapeutic strategies for the activation of inflammatory pathways and immune cells [180]. On the other hand, radiotherapy can cause changes in gene expression in various cells in the tumor microenvironment.…”

Pan-Cancer Analysis of Radiotherapy Benefits and Immune Infiltration in Multiple Human Cancers

“…For many years, in order to improve the outcomes of RT, most studies focused on mechanisms internal to the cancer cell (intrinsic radiosensitivity), ignoring complex interactions between the tumor and the TME in which it grows (extrinsic radiosensitivity) [19][20][21]. Moreover, pre-clinical studies in some tumor models have suggested that RT-induced changes in the TME might, in fact, promote tumor invasion and spread the tumor in certain situations [30][31][32].…”

“…On one hand, the effect of radiation on tumor cells could induce the release of new antigens and trigger the immune system to activate tumor-specific T cells. On the other hand, radiation could enhance TME immune infiltration, thereby overcoming some of the barriers to tumor rejection [19][20][21]. Cancer cells often express programmed cell death-ligand 1 (PD-L1) and subsequently induce T-cell apoptosis, and PD-L1 status is an important factor in the prediction of the clinical outcome following RT in BRCA patients [22].…”

Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition

“…Mitigation of these two immunosuppressive cells using CTX and L-NIL (CTX/L-NIL) ultimately promoted enhanced infiltration of CD8 + T cells and improved survival in a mouse model of melanoma [31]. In an additional murine model of human papillomavirus (HPV) head and neck squamous cell carcinoma (HPV-HNSCC) we observed that CTX/L-NIL promotes even broader immunologic effects, including the upregulation of numerous anti-tumoral immune pathways such as antigen processing and presentation, myeloid trafficking and activation, and T cell function and co-stimulation [32]. We further found that its combination with chemoradiotherapy promoted favorable alterations in both the myeloid and lymphoid intratumoral microenvironment which significantly enhanced the therapeutic benefit of standard-of-care therapy [32].…”

“…In an additional murine model of human papillomavirus (HPV) head and neck squamous cell carcinoma (HPV-HNSCC) we observed that CTX/L-NIL promotes even broader immunologic effects, including the upregulation of numerous anti-tumoral immune pathways such as antigen processing and presentation, myeloid trafficking and activation, and T cell function and co-stimulation [32]. We further found that its combination with chemoradiotherapy promoted favorable alterations in both the myeloid and lymphoid intratumoral microenvironment which significantly enhanced the therapeutic benefit of standard-of-care therapy [32]. Thus, we hypothesized that CTX/L-NIL immunomodulation could promote a “cold to hot” transition of the TIME which could enhance treatment responses to ICI and radiation therapies.…”