Combination Strategies to Augment Immune Check Point Inhibitors Efficacy - Implications for Translational Research

Varayathu, Hrishi; Sarathy, Vinu; Thomas, Beulah Elsa; Mufti, Suhail Sayeed; Naik, Radheshyam

doi:10.3389/fonc.2021.559161

Cited by 45 publications

(36 citation statements)

References 162 publications

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“…Other groups have corroborated our findings and reported other cancer cell-specific PD-1 activation of oncogenic signaling cascades [3,4,[6][7][8], which appear to be dependent on the cancer histology [4,6]. Building upon our body of work showing an oncogenic role for endogenous PD-1 expression in PDAC, we discovered that highly activated c-MET (MET, mesenchymal-epithelial transition factor) was regulated by PD-1/PD-L1 signaling in PDAC cells.…”

Section: Introductionsupporting

confidence: 89%

Endogenous Pancreatic Cancer Cell PD-1 Activates MET and Induces Epithelial-Mesenchymal Transition to Promote Cancer Progression

Harper

Lin

Qasem

et al. 2022

Cancers

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We recently demonstrated that immune checkpoint PD-1 was endogenously expressed in pancreatic ductal adenocarcinoma (PDAC) cells. Our data indicated that PD-1 proteins are not exclusive to immune cells and have unrecognized signal transduction cascades intrinsic to cancer cells. Building on this paradigm shift, we sought to further characterize PD-1 expression in PDAC. We utilized a phospho-explorer array to identify pathways upregulated by PD-1 signaling. We discovered PD-1-mediated activation of the proto-oncogene MET in PDAC cells, which was dependent on hepatocyte growth factor (MET ligand) and not secondary to direct protein interaction. We then discovered that the PD-1/MET axis in PDAC cells regulated growth, migration, and invasion. Importantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a well-established early oncogenic process in PDAC. We observed that combined targeting of PDAC cell PD-1 and MET resulted in substantial direct tumor cell cytotoxicity and growth inhibition in PDAC cell lines, patient-derived organoids, and patient-derived xenografts independent of cytotoxic immune responses. This is the first report of PDAC-endogenous PD-1 expression regulating MET signaling, which builds upon our growing body of work showing the oncogenic phenotype of PD-1 expression in PDAC cells is distinct from its immunogenic role. These results highlight a paradigm shift that the tumor-specific PD-1 axis is a novel target to effectively kill PDAC cells by antagonizing previously unrecognized PD-1-dependent oncogenic pathways.

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Section: Introductionsupporting

confidence: 89%

Endogenous Pancreatic Cancer Cell PD-1 Activates MET and Induces Epithelial-Mesenchymal Transition to Promote Cancer Progression

Harper

Lin

Qasem

et al. 2022

Cancers

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“…Preclinical and clinical trials have identified metabolic targeting drugs with the potential to enhance the efficacy of immune checkpoint blockade therapy [ 151 , 152 ]. The synergism of immune checkpoint blockade therapy combined with metformin against tumor burden has been demonstrated in preclinical studies [ 153 , 154 , 155 ].…”

Section: Clinical Perspective Of Immune Checkpoint Blockade Therapymentioning

confidence: 99%

Metabolic Implications of Immune Checkpoint Proteins in Cancer

Stirling

Bronson

Mackert

et al. 2022

Cells

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Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.

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“…Furthermore, it has been shown that the favorable immune effects mediated by BRAF/MEKi are paralleled by the induction of T cell exhaustion markers and, thus, treatment response appears to subside in the long-term [ 100 ]. Therefore, it has been proposed by a number of preclinical studies and clinical trials that the efficacy of ICI [ 106 ] and BRAFi/MEKi [ 19 , 107 ] may be considerably enhanced by co-administration of additional anti-tumor drugs (such as conventional chemo or radiotherapy), as well as agents which act on regulatory immune cells (i.e., antiangiogenic drugs, tyrosine kinase receptor antagonists).…”

Section: Conclusion/perspectivesmentioning

confidence: 99%

Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond

Jung

Haist

Kuske

et al. 2021

IJMS

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The advent of mitogen–activated protein kinase (MAPK) inhibitors that directly inhibit tumor growth and of immune checkpoint inhibitors (ICI) that boost effector T cell responses have strongly improved the treatment of metastatic melanoma. In about half of all melanoma patients, tumor growth is driven by gain–of–function mutations of BRAF (v–rat fibrosarcoma (Raf) murine sarcoma viral oncogene homolog B), which results in constitutive ERK activation. Patients with a BRAF mutation are regularly treated with a combination of BRAF and MEK (MAPK/ERK kinase) inhibitors. Next to the antiproliferative effects of BRAF/MEKi, accumulating preclinical evidence suggests that BRAF/MEKi exert immunomodulatory functions such as paradoxical ERK activation as well as additional effects in non–tumor cells. In this review, we present the current knowledge on the immunomodulatory functions of BRAF/MEKi as well as the non–intended effects of ICI and discuss the potential synergistic effects of ICI and MAPK inhibitors in melanoma treatment.

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Combination Strategies to Augment Immune Check Point Inhibitors Efficacy - Implications for Translational Research

Cited by 45 publications

References 162 publications

Endogenous Pancreatic Cancer Cell PD-1 Activates MET and Induces Epithelial-Mesenchymal Transition to Promote Cancer Progression

Endogenous Pancreatic Cancer Cell PD-1 Activates MET and Induces Epithelial-Mesenchymal Transition to Promote Cancer Progression

Metabolic Implications of Immune Checkpoint Proteins in Cancer

Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond

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