Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss how the context-specific nature of infiltrating immune cells can affect the prognosis of patients.

The immune contexture in human tumours: impact on clinical outcome

PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota. We further clarify the mechanisms of action of these markers and their roles in shaping, being shaped, and/or predicting therapeutic responses. We also discuss a variety of combinations with PD pathway blockade and their scientific rationales for cancer treatment.

PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations

High-dose ionizing irradiation (IR) results in direct tumor cell death and augments tumor-specific immunity, which enhances tumor control both locally and distantly. Unfortunately, local relapses often occur following IR treatment, indicating that IR-induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator programmed death–ligand 1 (PD-L1, also called B7-H1) can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors. Here, we demonstrate that PD-L1 was upregulated in the tumor microenvironment after IR. Administration of anti–PD-L1 enhanced the efficacy of IR through a cytotoxic T cell–dependent mechanism. Concomitant with IR-mediated tumor regression, we observed that IR and anti–PD-L1 synergistically reduced the local accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which suppress T cells and alter the tumor immune microenvironment. Furthermore, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumors through the cytotoxic actions of TNF. Our data provide evidence for a close interaction between IR, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and radiotherapy.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/67000/67313/JCI67313.v2.pdf

Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice

STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors

During the past two decades, the paradigm for cancer treatment has evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain the backbone of current treatment, but they are limited by a narrow therapeutic index, significant toxicities and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are crucial for tumour growth and maintenance; whereas, immunotherapy endeavours to stimulate a host immune response that effectuates long-lived tumour destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes.

Combining immunotherapy and targeted therapies in cancer treatment

http://www.ibp.cas.cn/wsdLab/wsdLabfblw/201210/W020121109449218072645.pdf

The Therapeutic Effect of Anti-HER2/neu Antibody Depends on Both Innate and Adaptive Immunity

Purpose: Targeting oncogenic receptors with antibodies has been thought to suppress tumor growth mainly by interrupting oncogenic signals. Recently, the essential role for adaptive immunity, and CD8 + T cells in particular, has been established as a major factor for anti-HER2/neu–mediated tumor regression. However, the role of CD4 + T cells is still being defined. The purpose of this study was to explore whether and to what extent CD4 + T cells are involved in mediating the effects of anti-HER2/neu therapy. Experimental Design: The role of CD4 + T cells was examined using a transplant model of the rat HER2/neu–overexpressing cell line TUBO. Tumor-bearing mice were treated with anti-neu therapy in conjunction with CD4 depletion or CD40L blockade. The effects of CD4 depletion on the antitumor response were examined by tumor growth analysis and enzyme-linked immunospot (ELISPOT). Results: In addition to CD8 + T cells, CD4 + T cells are also essential for anti-neu antibody-mediated tumor regression, but B cells are not required. The role for CD4 + cells is necessary throughout anti-neu therapy and not limited to helping CD8 + T cells. Expression of IFN-γ is necessary for anti-neu therapy and IFN-γ induces MHC-II expression in TUBO cells promoting direct recognition by CD4 + T cells. Furthermore, intratumoral depletion of CD4 + T cells or blockade of the activating cell-surface protein CD40L inhibits the antitumor response. Conclusions: This study reveals the essential role of CD4 + T cell for anti-neu–mediated tumor regression. Clin Cancer Res; 19(6); 1476–86. ©2013 AACR .

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Effective Anti-Neu–Initiated Antitumor Responses Require the Complex Role of CD4+ T Cells

Currently, an inactivated vaccine has been widely used with encouraging results as a prophylactic agent against COVID-19 infection, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. However, in vitro SARS-CoV-2 vaccine-specific immune features remain elusive, hindering the promotion of a third dose of the vaccine. Here, we present a detailed in vitro immune cellular response and large-scale multi-omics analysis for peripheral blood mononuclear cells (PBMCs) from participants vaccinated with CoronaVac (Sinovac Life Sciences, Beijing, China) and recovered participants from COVID-19. The mean titers of SARS-CoV-2 serum-neutralizing antibodies were significantly increased after the boosting immunization (Day 45) compared to the unimmunized state. We observed that type-1 helper T cells (Th1) tended to dominate after the first dose of vaccine, while humoral immune responses became dominant after the second dose due to the activation of type-2 helper T cell (Th2), memory B cells, and plasmablasts. T follicular helper cells (Tfh) involved in antibody production were activated after the first dose and were maintained for the observed time points. Single-cell RNA sequencing of PBMCs revealed specific changes in cell compositions and gene expression in immunized participants. Multi-omics analysis also demonstrated that CoronaVac-specific serum proteins, plasma metabolites, and plasma lipid changes were skewed to those changes in convalescent patients. Collectively, we provide a comprehensive understanding of CoronaVac-specific in vitro immune features.

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An Integrative Analysis of the Immune Features of Inactivated SARS-CoV-2 Vaccine (CoronaVac)

/pdf/force-test-in-a-large-scale-shock-tunnel-2m2nbja2vn.pdf

Force Test in a Large-Scale Shock Tunnel

Rationale: Cyclic dinucleotides (cDNs) are a promising class of immunotherapeutic agent targeting stimulator of interferon genes (STING). However, enzymatic instability and transmembrane barriers limit the extensive clinical application of cDNs. Thus, a novel delivery system, composed of a neutral cytidinyl lipid DNCA and a cationic lipid CLD (Mix) that interacts with cDNs via H-bonding, pi-stacking and electrostatic interaction, is developed and optimized to overcome the above issues. Methods: The optimal composition of Mix for cDNs encapsulation was explored with RAW-Lucia ISG cells. The physicochemical properties of resulted nanoparticles were characterized. To validate the anti-tumor immunity of cDNs/Mix both in vitro and in vivo, immunogenic cell death (ICD) related markers and tumor inhibition efficacy were evaluated in cancer cells and tumor models, respectively. The mechanism by which cdG/Mix exerted the antitumor effects was explored by flow cytometric analysis and in vivo depletion. Results: Based on our developed and optimized delivery system, neutral cytidinyl lipid DNCA/cationic lipid CLD (Mix), cdG (500 nM in vitro, 1-10 μg in vivo)/Mix not only more potently stimulated production of IFNβ and related cytokines including CXCL9 and CXCL10, promoted ICD, led to NK and CD8+ T cell activation, inhibited tumor growth in both EO771 and B16F10 models and increased their survival rate (~43%), but also obviously reversed the T cell exhaustion (Tex) in tumor, meanwhile down regulated the mRNA expression of Tox and Nr4a, which are key regulators of Tex. Conclusion: cdG/Mix triggered ICD in various cancer cells and reversed the Tex systemically in tumor-burden mice, which would be a promising alternative strategy for cancer immunotherapy.

Zhujun Jiang

Papers

The Therapeutic Effect of Anti-HER2/neu Antibody Depends on Both Innate and Adaptive Immunity

Effective Anti-Neu–Initiated Antitumor Responses Require the Complex Role of CD4+ T Cells

An Integrative Analysis of the Immune Features of Inactivated SARS-CoV-2 Vaccine (CoronaVac)

Force Test in a Large-Scale Shock Tunnel

Novel formulation of c-di-GMP with cytidinyl/cationic lipid reverses T cell exhaustion and activates stronger anti-tumor immunity