Author response for "The tumor microenvironment of lymphomas: insights into the potential role and modes of actions of checkpoint inhibitors"

The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.

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Expanded human NK cells from lung cancer patients sensitize patients’ PDL1−negative tumors to PD1-blockade therapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001933 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001933

Author(s):

Sophie M Poznanski ◽

Tyrah M Ritchie ◽

Isabella Y Fan ◽

Abdullah El-Sayes ◽

Ana L Portillo ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Microenvironment ◽

Nk Cells ◽

Tumor Regression ◽

Checkpoint Inhibitors ◽

Combined Treatment ◽

Death Receptor ◽

High Rate ◽

Advanced Lung Cancer ◽

Pd1 Blockade

Lung cancer remains the leading cause of cancer death worldwide despite the significant progress made by immune checkpoint inhibitors, including programmed death receptor-1 (PD1)/PD ligand 1 (PDL1)-blockade therapy. PD1/PDL1−blockade has achieved unprecedented tumor regression in some patients with advanced lung cancer. However, the majority of patients fail to respond to PD1/PDL1 inhibitors. The high rate of therapy non-response results from insufficient PDL1 expression on most patients’ tumors and the presence of further immunosuppressive mechanisms in the tumor microenvironment. Here, we sensitize non-responding tumors from patients with lung cancer to PD1-blockade therapy using highly cytotoxic expanded natural killer (NK) cells. We uncover that NK cells expanded from patients with lung cancer dismantle the immunosuppressive tumor microenvironment by maintaining strong antitumor activity against both PDL1+ and PDL1− patient tumors. In the process, through a contact-independent mechanism involving interferon γ, expanded NK cells rescued tumor killing by exhausted endogenous TILs and upregulated the tumor proportion score of PDL1 across patient tumors. In contrast, unexpanded NK cells, which are susceptible to tumor-induced immunosuppression, had no effect on tumor PDL1. As a result, combined treatment of expanded NK cells and PD1-blockade resulted in robust synergistic tumor destruction of initially non-responding patient tumors. Thus, expanded NK cells may overcome the critical roadblocks to extending the prodigious benefits of PD1-blockade therapy to more patients with lung cancer and other tumor types.

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Emerging Trends for Radio-Immunotherapy in Rectal Cancer

Cancers ◽

10.3390/cancers13061374 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1374

Author(s):

Claudia Corrò ◽

Valérie Dutoit ◽

Thibaud Koessler

Keyword(s):

Rectal Cancer ◽

Tumor Microenvironment ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Predictive Biomarkers ◽

Tumor Infiltrating Lymphocytes ◽

T Cell Infiltration ◽

Emerging Trends ◽

Tumor Mutational Burden ◽

Microsatellite Stability

Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.

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Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level?

International Journal of Molecular Sciences ◽

10.3390/ijms22042142 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2142

Author(s):

Rola El Sayed ◽

Yolla Haibe ◽

Ghid Amhaz ◽

Youssef Bouferraa ◽

Ali Shamseddine

Keyword(s):

Fatty Acid ◽

Tumor Microenvironment ◽

Immune Cells ◽

Immune Modulation ◽

Checkpoint Inhibitors ◽

Therapeutic Option ◽

Effector Memory ◽

Acid Oxidation ◽

Checkpoint Inhibition ◽

Inflammatory Phenotypes

Immunotherapy has changed the treatment paradigm in multiple solid and hematologic malignancies. However, response remains limited in a significant number of cases, with tumors developing innate or acquired resistance to checkpoint inhibition. Certain “hot” or “immune-sensitive” tumors become “cold” or “immune-resistant”, with resultant tumor growth and disease progression. Multiple factors are at play both at the cellular and host levels. The tumor microenvironment (TME) contributes the most to immune-resistance, with nutrient deficiency, hypoxia, acidity and different secreted inflammatory markers, all contributing to modulation of immune-metabolism and reprogramming of immune cells towards pro- or anti-inflammatory phenotypes. Both the tumor and surrounding immune cells require high amounts of glucose, amino acids and fatty acids to fulfill their energy demands. Thus, both compete over one pool of nutrients that falls short on needs, obliging cells to resort to alternative adaptive metabolic mechanisms that take part in shaping their inflammatory phenotypes. Aerobic or anaerobic glycolysis, oxidative phosphorylation, tryptophan catabolism, glutaminolysis, fatty acid synthesis or fatty acid oxidation, etc. are all mechanisms that contribute to immune modulation. Different pathways are triggered leading to genetic and epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking status, may be as well contributory to immune modulation, anti-tumor immunity and response to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function.

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