Chemokines are small secreted proteins that orchestrate migration and positioning of immune cells within the tissues. Chemokines are essential for the function of the immune system. Accumulating ...evidence suggest that chemokines play important roles in tumor microenvironment. In this review we discuss an association of chemokine expression and activity within the tumor microenvironment with cancer outcome. We summarize regulation of immune cell recruitment into the tumor by chemokine-chemokine receptor interactions and describe evidence implicating chemokines in promotion of the "inflamed" immune-cell enriched tumor microenvironment. We review both tumor-promoting function of chemokines, such as regulation of tumor metastasis, and beneficial chemokine roles, including stimulation of anti-tumor immunity and response to immunotherapy. Finally, we discuss the therapeutic strategies target tumor-promoting chemokines or induce/deliver beneficial chemokines within the tumor focusing on pre-clinical studies and clinical trials going forward. The goal of this review is to provide insight into comprehensive role of chemokines and their receptors in tumor pathobiology and treatment.
The rationale behind cancer immunotherapy is based on the unequivocal demonstration that the immune system plays an important role in limiting cancer initiation and progression. Adoptive cell therapy ...(ACT) is a form of cancer immunotherapy that utilizes a patient’s own immune cells to find and eliminate tumor cells, however, donor immune cells can also be employed in some cases. Here, we focus on T lymphocyte (T cell)-based cancer immunotherapies that have gained significant attention after initial discoveries that graft-versus-tumor responses were mediated by T cells. Accumulating knowledge of T cell development and function coupled with advancements in genetics and data science has enabled the use of a patient’s own (autologous) T cells for ACT (TIL ACTs). In TIL ACT, tumor-infiltrating lymphocytes (TILs) are collected from resected tumor material, enhanced and expanded
ex-vivo
, and delivered back to the patient as therapeutic agents. ACT with TILs has been shown to cause objective tumor regression in several types of cancers including melanoma, cervical squamous cell carcinoma, and cholangiocarcinoma. In this review, we provide a brief history of TIL ACT and discuss the current state of TIL ACT clinical development in solid tumors. We also discuss the niche of TIL ACT in the current cancer therapy landscape and potential strategies for patient selection.
Review on emerging combinations of immunotherapeutic agents, and treatment regimens which combine immunotherapy with drugs targeting cancer cells.
Immune‐checkpoint blockade therapy with antibodies ...targeting CTLA‐4 and PD‐1 has revolutionized melanoma treatment by eliciting responses that can be remarkably durable and is now advancing to other malignancies. However, not all patients respond to immune‐checkpoint inhibitors. Extensive preclinical evidence suggests that combining immune‐checkpoint inhibitors with other anti‐cancer treatments can greatly improve the therapeutic benefit. The first clinical success of the combinatorial approach to cancer immunotherapy was demonstrated using a dual‐checkpoint blockade with CTLA‐4 and PD‐1 inhibitors, which resulted in accelerated FDA approval of this therapeutic regimen. In this review, we discuss the combinations of current and emerging immunotherapeutic agents in clinical and preclinical development and summarize the insights into potential mechanisms of synergistic anti‐tumor activity gained from animal studies. These promising combinatorial partners for the immune‐checkpoint blockade include therapeutics targeting additional inhibitory receptors of T cells, such as TIM‐3, LAG‐3, TIGIT, and BTLA, and agonists of T cell costimulatory receptors 4‐1BB, OX40, and GITR, as well as agents that promote cancer cell recognition by the immune system, such as tumor vaccines, IDO inhibitors, and agonists of the CD40 receptor of APCs. We also review the therapeutic potential of regimens combining the immune‐checkpoint blockade with therapeutic interventions that have been shown to enhance immunogenicity of cancer cells, including oncolytic viruses, RT, epigenetic therapy, and senescence‐inducing therapy.
Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We ...hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.
Huseni et al. report that IL-6-STAT3 signaling negatively impacts the anti-tumor function of cytotoxic T cells. Targeting IL-6 signaling may enhance tumor responses to immune checkpoint blockade ...therapy.
Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that ...CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.
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•Breast cancer cells treated with CDK4/6 inhibitor secrete chemokines CCL5 and CXCL10•Chemokine induction is associated with deregulated mTOR, metabolic stress, and ROS•Chemokines induced by CDK4/6 inhibitor facilitate T cell infiltration into tumors•Chemokines induced by CDK4/6 inhibitor augment adoptive T cell therapy
Inhibitors of cell cycle kinases CDK4/6 delay progression of metastatic breast cancer; however, they do not eliminate tumors. Uzhachenko et al. report that metabolic changes in CDK4/6 inhibitor-treated cancer cells make them vulnerable to T cell therapies. These data highlight potential utility of CDK4/6 inhibitors to overcome immunotherapy resistance.
Tumor cell senescence is a common outcome of anticancer therapy. Here we investigated how therapy-induced senescence (TIS) affects tumor-infiltrating leukocytes (TILs) and the efficacy of ...immunotherapy in melanoma.
Tumor senescence was induced by AURKA or CDK4/6 inhibitors (AURKAi, CDK4/6i). Transcriptomes of six mouse tumors with differential response to AURKAi were analyzed by RNA sequencing, and TILs were characterized by flow cytometry. Chemokine RNA and protein expression were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Therapeutic response was queried in immunodeficient mice, in mice with CCL5-deficient tumors, and in mice cotreated with CD137 agonist to activate TILs. CCL5 expression in reference to TIS and markers of TILs was studied in human melanoma tumors using patient-derived xenografts (n = 3 patients, n = 3 mice each), in AURKAi clinical trial samples (n = 3 patients, before/after therapy), and in The Cancer Genome Atlas (n = 278). All statistical tests were two-sided.
AURKAi response was associated with induction of the immune transcriptome (P = 3.5 x 10-29) while resistance inversely correlated with TIL numbers (Spearman r = -0.87, P < .001). AURKAi and CDK4/6i promoted the recruitment of TILs by inducing CCL5 secretion in melanoma cells (P ≤ .005) in an NF-κB-dependent manner. Therapeutic response to AURKAi was impaired in immunodeficient compared with immunocompetent mice (0% vs 67% tumors regressed, P = .01) and in mice bearing CCL5-deficient vs control tumors (P = .61 vs P = .02); however, AURKAi response was greatly enhanced in mice also receiving T-cell-activating immunotherapy (P < .001). In human tumors, CCL5 expression was also induced by AURKAi (P ≤ .02) and CDK4/6i (P = .01) and was associated with increased immune marker expression (P = 1.40 x 10-93).
Senescent melanoma cells secret CCL5, which promotes recruitment of TILs. Combining TIS with immunotherapy that enhances tumor cell killing by TILs is a promising novel approach to improve melanoma outcomes.
While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to ...identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.
Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAF
and BRAF
melanoma and analyzed in reference to patient data.
RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8
cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40
SOX10
melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB.
Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.
NCT01205815 (Sept 17, 2010).
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