Are tumor-infiltrating lymphocytes protagonists or background actors in patient selection for cancer immunotherapy?

Marino, Federica Zito; Ascierto, Paolo A.; Rossi, Giulio; Staibano, Stefania; Montella, Marco; Russo, Daniela; Alfano, Roberto; Morabito, Alessandro; Botti, Gerardo; Franco, Renato

doi:10.1080/14712598.2017.1309387

Cited by 62 publications

(52 citation statements)

References 85 publications

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“…75−79 Although the exact explanation for the limited response rate is being researched, the current view is that responsiveness to immune checkpoint inhibitors is dependent on the presence of TILs that express immune checkpoint receptors. 11,80−83 Moreover, there appears to be a requirement for a high burden of nonsynonymous DNA mutations at the cancer site to develop a hot immune microenvironment. 10,11 These mutations give rise to potent neo-epitopes that are presented to T-cells by class I major histocompatibility complex on antigen-presenting dendritic cells.…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway

et al. 2018

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Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX). Intravenous injection of the encapsulated two-drug combination dramatically improved the pharmacokinetics and tumor drug concentrations of DOX and IND in an orthotopic 4T1 tumor model in syngeneic mice. Delivery of a threshold ICD stimulus resulted in the uptake of dying BC cells by dendritic cells, tumor antigen presentation and the activation/recruitment of naïve T-cells. The subsequent activation of perforin- and IFN-γ releasing cytotoxic T-cells induced robust tumor cell killing at the primary as well as metastatic tumor sites. Immune phenotyping of the tumor tissues confirmed the recruitment of CD8+ cytotoxic T lymphocytes (CTLs), disappearance of Tregs, and an increase in CD8+/FOXP3+ T-cell ratios. Not only does the DOX/IND-Liposome provide a synergistic antitumor response that is superior to a DOX-only liposome, but it also demonstrated that the carrier could be effectively combined with PD-1 blocking antibodies to eradicate lung metastases. All considered, an innovative nano-enabled approach has been established to allow deliberate use of ICD to switch an immune deplete to an immune replete BC microenvironment, allowing further boosting of the response by coadministered IDO inhibitors or immune checkpoint blocking antibodies.

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Section: Discussionmentioning

confidence: 99%

Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway

et al. 2018

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“…KALRNmutated cancers more highly express PD-L1, in addition to the increased anti-tumor immune infiltrates. Because both tumor-infiltrating lymphocyte density and PD-L1 expression are important factors in determining ICB therapy responsiveness 6,23 , it is reasonable for KALRNmutated cancers to exhibit increased susceptibility to ICB therapy. This was evidenced in four cancer cohorts receiving ICB therapy ( Figure 4C&4D).…”

Section: Discussionmentioning

confidence: 99%

KALRN Mutations Promote Anti-tumor Immunity and Immunotherapy Response in Cancer

Zhong

et al. 2020

Preprint

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Background: KALRN (kalirin RhoGEF kinase) is mutated in a wide range of cancers.Nevertheless, the association between KALRN mutations and the pathogenesis of cancer remains unexplored. The identification of biomarkers for cancer immunotherapy response is important considering that immunotherapies show beneficial effects only in a subset of cancer patients. Methods:We explored the correlation between KALRN mutations and anti-tumor immunity in 10 cancer cohorts from The Cancer Genome Atlas (TCGA) program by the bioinformatics approach. Moreover, we verified the findings from bioinformatics analysis by in vitro experiments. Furthermore, we explored the correlation between KALRN mutations and immunotherapy response in four cancer cohorts receiving immune checkpoint blockade therapy. Results:We found that anti-tumor immune signatures were stronger in KALRN-mutated than in KALRN-wildtype cancers. Moreover, KALRN mutations correlated with increased tumor mutation burden and the microsatellite instability or DNA damage repair deficiency genomic properties which may explain the elevated anti-tumor immunity in KALRN-mutated cancers.Furthermore, we found that PD-L1 expression was significantly upregulated in KALRN-mutated versus KALRN-wildtype cancers. The enhanced anti-tumor immune signatures and PD-L1 expression in KALRN-mutated cancers may favor the response to immune checkpoint blockade therapy in this cancer subtype, as evidenced in four cancer cohorts receiving anti-PD-1/PD-L1/ CTLA-4 immunotherapy. We further revealed that the significant association between KALRN mutations and increased anti-tumor immunity was attributed to that KALRN mutations compromised the function of KALRN target Rho GTPases on regulating DNA damage repair pathways. Conclusions:The KALRN mutation is a useful biomarker for predicting the response to immunotherapy in cancer patients.

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“…This theory of immunoediting was developed only recently . TILs are considered to reflect immunoediting . TILs are observed in several tumor types, including colorectal cancer, gastric cancer, hepatocellular carcinoma, bile duct cancer, and pancreatic cancer, which are reported to have prognostic value .…”

Section: Role Of Immune Cells In the Tumor Microenvironment Of Pancrementioning

confidence: 99%

Role of the tumor microenvironment in pancreatic cancer

Murakami

Hiroshima

Matsuyama

et al. 2019

Annals of Gastroent Surgery

121

100

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Pancreatic cancer remains a highly recalcitrant disease despite the development of systemic chemotherapies. New treatment options are thus urgently required. Dense stromal formation, so‐called “desmoplastic stroma,” plays controversial roles in terms of pancreatic cancer growth, invasion, and metastasis. Cells such as cancer‐associated fibroblasts, endothelial cells, and immune cells comprise the tumor microenvironment of pancreatic cancer. Pancreatic cancer is considered an immune‐quiescent disease, but activation of immunological response in pancreatic cancer may contribute to favorable outcomes. Herein, we review the role of the tumor microenvironment in pancreatic cancer, with a focus on immunological aspects.

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Are tumor-infiltrating lymphocytes protagonists or background actors in patient selection for cancer immunotherapy?

Cited by 62 publications

References 85 publications

Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway

Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway

KALRN Mutations Promote Anti-tumor Immunity and Immunotherapy Response in Cancer

Role of the tumor microenvironment in pancreatic cancer

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