scholarly journals Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2638
Author(s):  
Vito Amodio ◽  
Gianluca Mauri ◽  
Nicole M. Reilly ◽  
Andrea Sartore-Bianchi ◽  
Salvatore Siena ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Immune Evasion ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Clinical Samples ◽  
Primary Resistance ◽  
Mechanistic Basis ◽  
Sting Pathway ◽  
Beta 2 Microglobulin

Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs.

scholarly journals Roles of Extracellular HSPs as Biomarkers in Immune Surveillance and Immune Evasion

2019 ◽  
Vol 20 (18) ◽  
pp. 4588 ◽  
Author(s):  
Eman A. Taha ◽  
Kisho Ono ◽  
Takanori Eguchi
Keyword(s):  
Heat Shock ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Checkpoint Inhibitors ◽  
Membrane Surface ◽  
Immune Surveillance ◽  
Heat Shock Factor 1 ◽  
Heterochromatin Protein 1 ◽  
Liquid Biopsies

Extracellular heat shock proteins (ex-HSPs) have been found in exosomes, oncosomes, membrane surfaces, as well as free HSP in cancer and various pathological conditions, also known as alarmins. Such ex-HSPs include HSP90 (α, β, Gp96, Trap1), HSP70, and large and small HSPs. Production of HSPs is coordinately induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), while matrix metalloproteinase 3 (MMP-3) and heterochromatin protein 1 are novel inducers of HSPs. Oncosomes released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP) by which immune evasion can be established. The concepts of RASP are: (i) releases of ex-HSP and HSP-rich oncosomes are essential in RASP, by which molecular co-transfer of HSPs with oncogenic factors to recipient cells can promote cancer progression and resistance against stresses such as hypoxia, radiation, drugs, and immune systems; (ii) RASP of tumor cells can eject anticancer drugs, targeted therapeutics, and immune checkpoint inhibitors with oncosomes; (iii) cytotoxic lipids can be also released from tumor cells as RASP. ex-HSP and membrane-surface HSP (mHSP) play immunostimulatory roles recognized by CD91+ scavenger receptor expressed by endothelial cells-1 (SREC-1)+ Toll-like receptors (TLRs)+ antigen-presenting cells, leading to antigen cross-presentation and T cell cross-priming, as well as by CD94+ natural killer cells, leading to tumor cytolysis. On the other hand, ex-HSP/CD91 signaling in cancer cells promotes cancer progression. HSPs in body fluids are potential biomarkers detectable by liquid biopsies in cancers and tissue-damaged diseases. HSP-based vaccines, inhibitors, and RNAi therapeutics are also reviewed.

scholarly journals Differential kynurenine pathway metabolism in highly-metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression

2020 ◽  
Author(s):  
Benjamin Heng ◽  
Ayse A. Bilgin ◽  
David B Lovejoy ◽  
Vanessa X Tan ◽  
Heloisa Helena Milioli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Kynurenine Pathway ◽  
Clinical Samples ◽  
Tumor Immune Evasion ◽  
Cancer Subtypes ◽  
Metabolomic Profiling ◽  
Promising Treatment ◽  
Aggressive Breast Cancer

Abstract Background: Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanism(s) to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa.Methods: To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1,997) that represent major subtypes of BrCa (luminal, HER2, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry and ultra-high pressure liquid chromatography on these samples to quantify KP enzyme gene, protein and activity respectively.Results: We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA).Conclusions: Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

Prevalence of NTRK1/3 fusions in mismatch repair-deficient (dMMR)/microsatellite instable (MSI) tumors of patients with metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15537-e15537
Author(s):  
Magali Svrcek ◽  
Raphael Colle ◽  
Anne Cayre ◽  
Pierre Bourgoin ◽  
Romain Cohen ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Methylation Status ◽  
Cell Of Origin ◽  
Primary Resistance ◽  
Paired Samples ◽  
Repair Deficiency ◽  
Innovative Therapies ◽  
Radiological Response ◽  
Negative Tumor

e15537 Background: Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic TRK ( NTRK) fusion-driven cancers, regardless of tumor histotype or cell of origin. NTRK gene fusions are observed in less than 1% of colorectal cancers (CRCs). CRCs harboring wild-type BRAF and KRAS and MisMatch Repair deficiency (dMMR)/MicroSatellite Instability (MSI) due to MLH1 hypermethylation have been associated with NTRK fusions in small cohorts of non-metastatic tumors. We aimed at evaluating the incidence of NTRK fusions among dMMR/MSI metastatic CRCs (mCRC) for which there is a need for innovative therapies, as well as the associated clinical characteristics of these patients (pts) carrying NTRK fusion-positive tumors. Methods: Tumor samples of dMMR/MSI mCRC pts, paired primary and metastasis or primary alone, were obtained from a French multicenter retrospective cohort and from a single-center cohort of patients treated by immune checkpoint inhibitors (ICI) (Saint-Antoine Hospital, Paris). Clinico-pathological data including KRAS and BRAFV600E status, MMR proteins and MLH1 methylation status were available for all pts. All samples were screened for TRK expression by immunohistochemistry (IHC) using a pan-TRK antibody (clone EPR17341, Abcam; positivity: 1% of labeled tumor cells)) and for NTRK1 and NTRK3 gene rearrangements, by fluorescent in situ hybridation (FISH). A threshold of 15% nuclei positive for a break apart signal was considered positive for gene rearrangement. Results: A total of 158 pts with dMMR/MSI mCRCs (paired samples: n=39; primary only: n=119) were screened. Tumor samples of 10 patients (6.3%) harbored NTRK fusion genes by FISH ( NTRK1=8; NTRK3=2). Only four of these 10 patients had TRK immunoreactivity. One patient showed a discordance between metastasis harboring NTRK1 fusion (+) and primary tumor being negative. Eight tumors were sporadic with MLH1 hypermethylation. The remaining 2 cases were related to a MMR gene germline mutation (Lynch syndrome) with concurrent loss of MSH2 and MSH6 expression and isolated loss of MSH6 respectively. One Lynch-related tumor was KRAS mutated, one sporadic MLH1-negative tumor was BRAF V600E mutated. Four patients out of 91 treated by ICI had tumors with NTRK fusions. Three have shown radiological response according to iRECIST criteria (two complete responses, one partial response with 25 to 54 months of follow up) and one had primary resistance to ICI. Conclusions: Frequency of NTRK1/3 fusions is 6.3% in our dMMR/MSI mCRCs population. These fusions are not restricted to sporadic cases. The diagnostic accuracy of pan-TRK IHC is low. Optimal testing algorithms for theragnostics remain to be defined in this setting.

scholarly journals Immune Therapy Resistance and Immune Escape of Tumors

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 551
Author(s):  
Barbara Seliger ◽  
Chiara Massa
Keyword(s):  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Immune Therapy ◽  
Immune Surveillance ◽  
Therapy Resistance ◽  
The Novel ◽  
Major Goal ◽  
Immune Mediated ◽  
Tumor Clearance

Immune therapy approaches such as checkpoint inhibitors or adoptive cell therapy represent promising therapeutic options for cancer patients, but their efficacy is still limited, since patients frequently develop innate or acquired resistances to these therapies. Thus, one major goal is to increase the efficiency of immunotherapies by overcoming tumor-induced immune suppression, which then allows for immune-mediated tumor clearance. Innate resistance to immunotherapies could be caused by a low immunogenicity of the tumor itself as well as an immune suppressive microenvironment composed of cellular, physical, or soluble factors leading to escape from immune surveillance and disease progression. So far, a number of strategies causing resistance to immunotherapy have been described in various clinical trials, which broadly overlap with the immunoediting processes of cancers. This review summarizes the novel insights in the development of resistances to immune therapy as well as different approaches that could be employed to overcome them.

scholarly journals Roles of Extracellular Vesicles (EVs) Carrying HSPs in Cancer Biomarkers, Immune Surveillance, and Immune Evasion

2019 ◽  
Author(s):  
Eman Taha ◽  
Kisho Ono ◽  
Takanori Eguchi
Keyword(s):  
Heat Shock ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Heat Shock Factor 1 ◽  
Targeted Therapeutics ◽  
Heterochromatin Protein 1

Extracellular vesicles (EV) released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP), by which immune evasion can be established. Heat shock proteins (HSPs) are an evolutionarily conserved family of molecular chaperones, which stabilize proteins, minimize protein misfolding and aggregation within the cell, besides facilitating protein translocation, refolding and degradation. (i) Releases of extracellular HSPs (ex-HSP) and EV-associated HSPs (EV-HSP) are essential in RASP, by which molecular cotransfer of HSPs with oncogenic factors into recipient cells can promote cancer progression and resistance against stress such as hypoxia, radiation, chemicals, and immune system. (ii) RASP of tumor cells can eject anticancer drugs, molecularly targeted therapeutics, and immune checkpoint inhibitors with EVs. (iii) Cytotoxic lipids can be also released from tumor cells as RASP. Nevertheless, ex-HSP and EV-HSP can play immunostimulatory and immunosuppressive roles by binding to receptors such as LRP1/CD91/A2MR, scavenger receptors, and toll-like receptors expressed on recipient cells. Liquid biopsy of HSPs in body fluids may be useful in diagnosis, prognosis, and treatment in cancer. Regarding HSP90-targeted therapeutics, we summarize the pros, cons, and problem solutions in this review. Although production of HSPs are canonically induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), recent studies discovered that production of HSPs is also regulated by matrix metalloproteinase 3 (MMP3) and heterochromatin protein 1 (HP1) and production of cochaperone CDC37 is reciprocally regulated by myeloid zinc finger 1 (MZF1) and SCAN-D1.

scholarly journals Differential kynurenine pathway metabolism in highly-metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression

2020 ◽  
Author(s):  
Benjamin Heng ◽  
Ayse A. Bilgin ◽  
David B Lovejoy ◽  
Vanessa X Tan ◽  
Heloisa Helena Milioli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Kynurenine Pathway ◽  
Clinical Samples ◽  
Tumor Immune Evasion ◽  
Cancer Subtypes ◽  
Metabolomic Profiling ◽  
Promising Treatment ◽  
Aggressive Breast Cancer

Abstract Background: Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanism(s) to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa.Methods: To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1,997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry and ultra-high pressure liquid chromatography on these samples to quantify KP enzyme gene, protein and activity respectively.Results: We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA).Conclusions: Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

scholarly journals Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Benjamin Heng ◽  
Ayse A. Bilgin ◽  
David B. Lovejoy ◽  
Vanessa X. Tan ◽  
Heloisa H. Milioli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Kynurenine Pathway ◽  
Clinical Samples ◽  
Tumor Immune Evasion ◽  
Cancer Subtypes ◽  
Metabolomic Profiling ◽  
Promising Treatment ◽  
Aggressive Breast Cancer

Abstract Background Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa. Methods To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these samples to quantify the KP enzyme gene, protein, and activity, respectively. Results We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA). Conclusions Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

scholarly journals Low neoantigen expression and poor T cell priming underlie early immune escape in cancer

2020 ◽  
Author(s):  
Peter Westcott ◽  
Nathan Sacks ◽  
Jason Schenkel ◽  
Olivia Smith ◽  
Daniel Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Evasion ◽  
Immune Escape ◽  
Critical Role ◽  
Immune Surveillance ◽  
Tumor Rejection ◽  
Variable Expression ◽  
High Affinity ◽  
T Cell Priming

Abstract Immune evasion is a hallmark of cancer, and therapies that restore immune surveillance have proven highly effective in cancers with high tumor mutation burden (TMB) (e.g. microsatellite instable (MSI) colorectal cancer (CRC)). Whether low TMB cancers, which are largely refractory to immunotherapy, harbor T cell neoantigens capable of engaging adaptive immunity remains unclear. Here, we show that the majority of microsatellite stable (MSS) CRC harbors predicted high-affinity neoantigens despite low TMB. Unexpectedly, these neoantigens are broadly expressed at lower levels relative to those in MSI CRC, suggesting a potential role of antigen expression in tumor immune surveillance. To test this, we developed a versatile platform for functional interrogation of neoantigens with variable expression and applied it to novel preclinical colonoscopy-guided mouse models of CRC. While high expression of multiple high-affinity MHC-I-restricted neoantigens universally resulted in tumor rejection, low expression resulted in poor T cell priming and tumor progression. Strikingly, experimental or therapeutic rescue of priming rendered T cells fully capable of controlling tumors with low neoantigen expression. These findings underscore a critical role of neoantigen expression levels in immune evasion and suggest that poor expression or presentation may be a general feature of neoantigens acquired early in tumorigenesis. Finally, poorly expressed neoantigens, commonly excluded in tumor vaccine pipelines, may hold untapped therapeutic potential.

Epigenetic alternate promoter utilization and association with PD-L1 expression in Epstein–Barr virus positive gastric cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15509-e15509
Author(s):  
Raghav Sundar ◽  
Aditi Qamra ◽  
Angie Lay Keng Tan ◽  
Shenli Zhang ◽  
Cedric Chuan Young Ng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Epstein Barr Virus ◽  
Checkpoint Inhibitors ◽  
Primary Resistance ◽  
Barr Virus ◽  
Alternate Promoter ◽  
Epstein Barr ◽  
Gastric Cancer Patients

e15509 Background: We recently elicited the role of epigenetic promoter alterations as a mechanism of immune-evasion and primary resistance to immune checkpoint inhibition in gastric cancer. High prevalence of epigenetic modifications are known to occur in Epstein-Barr virus associated gastric cancer (EBVaGC). EBVaGC has high response rates to anti-PD-1 immune checkpoint inhibitors and is associated with high levels of PD-L1 expression. However, not all EBVaGC express PD-L1 and mechanisms that mediate these phenomena are unknown. Methods: We performed NanoString profiling and PD-L1 immunohistochemistry (using Dako PD-L1 IHC 22C3) on tissue from gastric cancer patients undergoing primary tumor resections at Samsung Medical Centre, South Korea. NanoString panel was designed for 90 recurrent somatic alternate promoter-related genes, and immune-related genes including PD-L1. EBV status was determined using EBV-encoded RNA in situ hybridization and categorized as EBVaGC and EBV-negative. Samples in the top-quartile of alternate promoter utilization were classified as APhigh and the remaining APlow. Results: A total of 272 samples (EBVaGC n = 79; EBV-negative n = 193) were included in this study. EBVaGC had significantly higher PD-L1 expression (p < 0.001) compared to EBV-negative samples. APhigh group (n = 67) consisted of 61 EBV-negative and 6 EBVaGC samples. EBVaGC APhigh tumors had significantly lower PD-L1 transcript expression compared to EBVaGC APlow tumors (p = 0.011, Wilcoxon-rank sum). Similar correlation was also found with PD-L1 IHC combined positive score (CPS)(median CPS score 1 vs 8, p = 0.047). There was a trend towards poorer survival for EBVaGC APhigh tumors (vs EBVaGC APlow; HR 0.23, 95% CI: 0.046 – 1.23, p = 0.087). EBV-negative APhigh tumors also had lower PD-L1 expression (vs EBV-negative APlow; p = 0.046, Wilcoxon-rank sum). Conclusions: Increased utilization of epigenetic alternate promoter isoforms correlates with lower transcriptomic and protein expression of PD-L1 in EBVaGC. Here we describe a potential mechanism of immune-evasion to explain low immune-infiltration and PD-L1 expression that occurs in a group of EBVaGC that is traditionally considered highly immunogenic.

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