The immune modifying effects of chemotherapy and advances in chemo-immunotherapy

Abstract

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for several malignancies. While the use of single-agent or combined ICIs has achieved acceptable disease control rates in a variety of solid tumors, such approaches have yet to show substantial therapeutic efficacy in select difficult-to-treat cancer types. Recently, select chemotherapy regimens are emerging as extensive modifiers of the tumor microenvironment, leading to the reprogramming of local immune responses. Accordingly, data is now emerging to suggest that certain anti-neoplastic agents modulate various immune cell processes, most notably the cross-presentation of tumor antigens, leukocyte trafficking, and cytokine biosynthesis. As such, the combination of ICIs and cytotoxic chemotherapy are beginning to show promise in many cancers that have long been considered poorly responsive to ICI-based immunotherapy. Here, we discuss past and present attempts to advance chemo-immunotherapy in these difficult-to-treat cancer histologies, mechanisms through which select chemotherapies modify tumor immunogenicity, as well as important considerations when designing such approaches to maximize efficacy and improve therapeutic response rates.

Keywords: Cancer; Chemotherapy; Immune checkpoint inhibitors; Immunology; Tumor microenvironment.

Figure 1.. Cyclophosphamide-mediated depletion of regulatory T-lymphocytes.

The immunogenic effects of cyclophosphamide (CP) are well documented, and much of the early rationale for combining chemotherapy and immunotherapy stemmed from observations that cyclophosphamide chemotherapy can deplete tumor-associated regulatory T-lymphocytes (Tregs). This specialized T-cell subpopulation acts to inhibit sterilizing immune responses and maintain peripheral tolerance. Tregs are highly sensitive to cyclophosphamide compared to effector T-cells, and cyclophosphamide has long been suggested as a potential means of targeting Tregs to potentiate cancer immunotherapy.

Figure 2.. Chemotherapy-induced HLA Class I expression enhances anti-tumor immune responses.

The loss of HLA Class I (HLA-I) is a widely utilized mechanism for immune evasion in cancer, impeding the ability of cytotoxic T-lymphocytes to recognize and destroy tumor cells. Several chemotherapy agents have been shown to augment tumor cell expression of HLA-I. While most studies to date have focused on platinum-based medications such as cisplatin and oxaliplatin, emerging data also supports a pro-antigen presentation role for non-platinum-based chemotherapy. Thus, by increasing the expression of HLA-I on the tumor cell surface, chemotherapy can potentially lead to the enhanced antigen presentation capacity of tumor cells, thereby allowing for more efficient priming of cytotoxic T-cells and improving therapeutic responses to ICI-based immunotherapy. Abbreviations: T-cell receptor (TCR); Granzyme B (GZMB), Perforin 1 (PRF1); Interferon γ (IFNγ).

Figure 3.. Chemotherapy-induced immunogenic cell death mobilizes tumor-antigen

In addition to enhancing HLA Class I-dependent antigen presentation, several chemotherapy medications can also promote immunogenic cell death. This process improves the availability of damage-associated molecular patterns (DAMPs) within the TME, thereby increasing the availability of tumor-antigen to professional antigen-presenting cells (APCs) and augmenting anti-tumor T-cell responses. The mechanisms through which chemotherapy induces immunogenic cell death are complex and, like more conventional antigen presentation, are best studied for platinum-based medications.

Figure 4.. Chemotherapy-induced PD-L1 expression as a means of immune escape

Though chemotherapy can enhance tumor cell immunogenicity and potentiate immune-stimulating processes, such as antigen presentation, several chemotherapy agents can also enhance the expression of negative immune checkpoints, importantly PD-L1. In this context, PD-L1 can associate with the PD-1 receptor on effector T-cells, blunting anti-tumor immune responses and facilitating immune escape. This ligand/receptor interaction is neutralized by antibodies against PD-1 (e.g., pembrolizumab and nivolumab) or PD-L1 (e.g., atezolizumab, avelumab, and durvalumab), and several combinations of chemotherapy and anti-PD-1/PD-L1 antibodies are either in clinical use or under clinical evaluation. Abbreviations: Granzyme B (GZMB), Perforin 1 (PRF1); Interferon γ (IFNγ).

Figure 5.. Chemotherapy enhances local cytokine synthesis and can facilitate lymphocyte trafficking into the tumor microenvironment

Several reports suggest that various chemotherapy medications can modulate tumor cytokine synthesis. For many cancers, chemotherapy can increase local levels of immune-stimulating cytokines/chemokines, thereby enhancing the recruitment of effector T-cells and promoting anti-tumor immunity. However, other reports suggest that chemotherapy often has contradictory roles regarding the local cytokine milieu and can also increase the release of several immune-suppressive signaling molecules. Hence, the success of future combination strategies may require the selective inhibition of chemotherapy-induced immune suppression in order to take full advantage of its immune-stimulating effects.