The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Basic Tumor Immunology Co-Section Editor, Dr. Sjoerd van der Burg.
“MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells” by Emeric Limagne et al
Cancer Cell (2022)
Despite well-characterized induction of immunogenic cell death (ICD) with some chemotherapies, many non-small cell lung cancers do not respond to chemoimmunotherapy. Emeric Limagne et al demonstrate a mechanism by which MEK inhibition may overcome chemoimmunotherapy resistance. In LLC1 murine lung carcinoma, pemetrexed plus cisplatin induced ICD markers in vitro and in vivo, but did not improve the efficacy of PD-L1 blockade and tumors had low expression of Cxcl9/10 chemokines as well as sparse CD8+ T cell infiltration. In a drug screen including 29 kinase inhibitors currently used in clinical practice, MEK1/2 inhibition was identified as increasing Cxcl10 mRNA expression and CXCL10 protein secretion in pemetrexed/cisplatin-exposed lung cancer cells. In murine urethane-induced lung cancers, adding a MEK inhibitor to pemetrexed/cisplatin plus anti-PD-L1 therapy enhanced tumor growth inhibition. Knockout of ATG5, a critical autophagy-mediating protein, resulted in lower Cxcl10 mRNA and CXCL10 protein expression following treatment with pemetrexed/cisplatin plus MEK inhibition. In a dose- and time-dependent manner, MEKi enhanced pemetrexed/cisplatin-induced mitophagy, which was correlated with increased Cxcl10 mRNA. Knockout of the selective mitophagy mediator optineurin impaired the ability of LLC1 cells to produce CXCL10 following treatment with pemetrexed/cisplatin and MEK inhibition. Depletion of mtDNA decreased Cxcl10 expression following treatment with pemetrexed/cisplatin and MEK inhibition, and TLR9 was required for full efficacy of the combination. MEK inhibition enhanced CXCL10 expression after pemetrexed/cisplatin in human lung cancer cell lines and in some cohorts of lung cancer patients who received a chemotherapy doublet followed by anti-PD-1 monotherapy, high expression of CXCL10 or optineurin was associated with improved PFS.
Why this matters: MEK inhibition offers a potential strategy to overcome tumor resistance to chemoimmunotherapy by increasing mitophagy. This leads to increased TLR9-mediated production of CXCL10 by tumor cells and consequently in the recruitment of CD8+ T cells to the tumor microenvironment, restoring immunologically hot s.
“Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors” by Fotis Nikolos et al
Nature Communications (2022)
Combining chemotherapy with immunotherapy has improved outcomes in several cancers, including breast and non-small cell lung cancer. Unfortunately, trials investigating this strategy in muscle-invasive bladder cancer (MIBC) did not show an improvement in outcomes compared to chemotherapy alone. To investigate the mechanism behind resistance to chemoimmunotherapy in this setting, Fotis Nikolos and colleagues developed two transplantable immune-excluded tumor models. In mice, gemcitabine-cisplatin (GC) chemotherapy did not effectively control tumor growth nor lead to robust cytotoxic T cell infiltration for either model. Furthermore, infiltrating dendritic cells were not activated or mature. GC treatment led to upregulation of COX-2 and release of the inhibitory danger associated molecular pattern PGE2 both in vivo and in vitro. The addition of celecoxib, a COX-2 inhibitor, to GC restored dendritic cell maturation, immune cell infiltration of tumors, and T cell cytotoxicity. Combination GC plus celecoxib treatment led to markedly improved tumor growth control compared to chemotherapy alone. The addition of anti-PD-1 to GC plus celecoxib further inhibited tumor growth for one of the models. Interestingly, analysis of pre-treatment samples from patients with MIBC from the IMvigor210 trial where patients received ICI after disease progression on platinum-based chemotherapy found an association between high pre-treatment expression of the gene encoding COX-2 and lack of benefit with ICIs.
Why this matters: This study provides new insight into immunomodulatory mechanisms of chemotherapy, indicating that in addition to the beneficial immunomodulatory effects of chemotherapy, other unwanted counterproductive mechanisms may also come into play. Identification and inhibition of those counterproductive mechanisms represents a potential strategy to reach the full potential of chemotherapy to convert immune-excluded into T cell-inflamed tumors.
“Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses” by Kunle Odunsi et al
Sci Transl Med (2022)
Preclinical evidence that IDO1 inhibitors combined with immune checkpoint inhibitors efficiently controlled tumors in cancers with high IDO1 expression was not borne out in phase III trials. Kunle Odunsi and colleagues add insight into mechanisms of treatment failure through multi-omics analysis of pre- and post-treatment tumor samples from 17 patients with ovarian cancer enrolled in a window of opportunity trial who the IDO1 inhibitor epacadostat prior to standard of care tumor debulking surgery and platinum-based chemotherapy. IDO1 is involved in tryptophan (Trp) catabolism along the kynurenine (Kyn) pathway, resulting in a conversion from Trp to Kyn. Metabolic and transcriptomic analyses after treatment with epacadostat elucidated dramatic perturbations in several metabolic pathways, resulting in a decrease in the Kyn pathway and increased serotonin and nicotinamide (Nic)/Nic adenine dinucleotide (NAD+) biosynthesis. This was driven by an increase in glutamine metabolism through the tricarboxylic acid (TCA) cycle, an increase in pentose-phosphate pathway synthesis of pyrimidine/purines, as well as other pathways converging to support NAD+ synthesis. Interestingly, IDO1 inhibition resulted in increased CD8+ T cell infiltration and IDO1 expression in some patients. However effector function was inhibited as the frequency of interferon-y and interleukin-2 expressing cells was reduced. In an orthotopic mouse model, the combination of epacadostat with FK866, an inhibitor of one NAD+ synthesis pathway, did not alter tumor growth compared to epacadostat alone. However, inhibition of the A2a and A2b purinergic receptors for which the NAD+ metabolite are ligands, increased survival and immune infiltration.
Why this matters: This study is a testimony to the adaptivity of tumors to treatments that interfere with immune regulatory pathways. The identified biochemical adaptations in metabolic pathways leading to IDO1 blockade-resistance, potentially opens the door to combination therapies that circumvent these secondary therapy resistance mechanisms.
“Neoadjuvant Intravenous Oncolytic Vaccinia Virus therapy Promotes Anti-Cancer Immunity in Patients” by Adel Samson et al
Cancer Immunology Research (2022)
In a phase Ib study, Adel Samson et al administered a single intravenous dose (1x109 pfu) of Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) an oncolytic GM-CSF-expressing, thymidine kinase-deleted vaccinia virus to nine patients with either colorectal cancer liver metastases (CRLM) or metastatic melanoma 10 to 22 days prior to planned surgery. Only one patient did not undergo surgery due to new sites of metastases prior to surgery. Pexa-Vec was detected in the plasma compartment of the peripheral blood only, and anti-Pexa-Vec antibodies peaked at the time of or one month after surgery. Pexa-Vec was detected in 4 out of 5 resected assessable tumors, and was detected only in a scattered, non-productive pattern in samples of background liver tissue. Pexa-Vec-related grade 3 or 4 adverse events included lymphopenia and neutropenia. Following Pexa-Vec infusion, there were increases in peripheral blood pro-inflammatory, pro-apoptotic, and dendritic cell maturation-associated cytokines, expression of interferon-stimulated genes, and NK cell activation, with a significant reduction of NK cell activation and function upon depletion of peripheral blood mononuclear cell (PBMNC) monocytes. A peak in plasma CXCL10 protein level was noted 24 hours following Pexa-Vec infusion and all resected tumors displayed CD8+ T cells. An increase in TAA-specific IFN-gamma-producing PBMCs was observed following Pexa-Vec infusion with TAA-specific T cell responses peaking at one month post-surgery and T cell responses remaining elevated for at least 3 months. T cell diversity was significantly lower for the two patients whose resected tumor displayed necrosis, with no difference in PBMC IFN-gamma response to Pexa-Vec between a necrotic and non-necrotic tumor.
Why this matters: These findings demonstrate that neoadjuvant systemic oncolytic viral therapy may facilitate long-lived anti-cancer immunity following surgery. It highlights the importance of applying this form of immunotherapy before surgical removal of the tumor, as recently also demonstrated with other classes of immunotherapeutic agents.
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