Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient ...survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.
Cancer immunotherapy has entered in a new era with the development of first-generation immune checkpoint inhibitors targeting the PD1/PD-L1 and CTLA-4 pathways. In this context, considerable research ...effort is being deployed to find the next generation of cancer immunotherapeutics. The CD73-adenosine axis constitutes one of the most promising pathways in immuno-oncology. We and others have demonstrated the immunosuppressive role of CD73-adenosine in cancer and established proof-of-concept that the targeted blockade of CD73 or adenosine receptors could effectively promote anti-tumor immunity and enhance the activity of first-generation immune checkpoint blockers. With Phase I clinical trials now underway evaluating anti-CD73 or anti-A2A therapies in cancer patients, we here discuss the fundamental, preclinical and clinical findings related to the role of the CD73-adenosinergic pathway in tumor immunity.
Four studies recently reported in the New England Journal of Medicine highlight advances in treatment with immune checkpoint blockade across the cancer care continuum. These findings demonstrate ...efficacy of these agents in the treatment of early and late-stage disease, as monotherapy or in combination, and in addition to—or in place of—standard front-line therapy.
Four studies recently reported in the New England Journal of Medicine highlight advances in treatment with immune checkpoint blockade across the cancer care continuum. These findings demonstrate efficacy of these agents in the treatment of early and late-stage disease, as monotherapy or in combination, and in addition to—or in place of—standard front-line therapy.
PD-1 blockade represents a major therapeutic avenue in anticancer immunotherapy. Delineating mechanisms of secondary resistance to this strategy is increasingly important. Here, we identified the ...deleterious role of signaling via the type I interferon (IFN) receptor in tumor and antigen presenting cells, that induced the expression of nitric oxide synthase 2 (NOS2), associated with intratumor accumulation of regulatory T cells (Treg) and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody (mAb). Sustained IFNβ transcription was observed in resistant tumors, in turn inducing PD-L1 and NOS2 expression in both tumor and dendritic cells (DC). Whereas PD-L1 was not involved in secondary resistance to anti-PD-1 mAb, pharmacological or genetic inhibition of NOS2 maintained long-term control of tumors by PD-1 blockade, through reduction of Treg and DC activation. Resistance to immunotherapies, including anti-PD-1 mAb in melanoma patients, was also correlated with the induction of a type I IFN signature. Hence, the role of type I IFN in response to PD-1 blockade should be revisited as sustained type I IFN signaling may contribute to resistance to therapy.
The human microbiome is a complex aggregate of microorganisms, and their genomes exert a number of influences crucial to the metabolic, immunologic, hormonal, and homeostatic function of the host. ...Recent work, both in preclinical mouse models and human studies, has shed light on the impact of gut and tumor microbiota on responses to systemic anticancer therapeutics. In light of this, strategies to target the microbiome to improve therapeutic responses are underway, including efforts to target gut and intratumoral microbes. Here, we discuss mechanisms by which microbiota may impact systemic and antitumor immunity, in addition to outstanding questions in the field. A deeper understanding of these is critical as we devise putative strategies to target the microbiome.
Immunotherapy Comes of Age in Lung Cancer Khanna, Priyanka, MD; Blais, Normand, MD, MSc, FRCPC; Gaudreau, Pierre-Olivier, M.D., FRCPC, M.Ps ...
Clinical lung cancer,
01/2017, Letnik:
18, Številka:
1
Journal Article
Recenzirano
Abstract Lung carcinoma is the leading cause of death by cancer worldwide. When possible, surgery is the best treatment strategy of patients with non-small cell lung cancer (NSCLC). However, even ...with curative-intent therapy, most patients will develop local or systemic recurrence and ultimately, succumb to their disease. In recent years, evidence on the role of the antitumour activity of the immune system and the understanding of tumour immunosurveillance, have resulted in the emergence of immunotherapy as a promising therapeutic approach in lung cancer. The main approaches are: immune checkpoint inhibition, such as the blockade of the cytotoxic T-lymphocyte antigen-4 (CTLA-4), and the programmed cell death-1 (PD-1) receptor and the PD-1 ligand, and vaccine therapy, which elicit specific antitumour immunity against relevant tumour-associated antigens. In this article, we review recently reported results from clinical trials, as well as the possible future role of vaccine therapy and immune checkpoint inhibition in the treatment of small cell lung cancer (SCLC) and NSCLC patients.
With the advent of immunotherapy as one of the keystones of the treatment of our patients with cancer, a number of atypical patterns of response to these agents has been identified. These include ...pseudoprogression, where the tumor initially shows objective growth before decreasing in size, and hyperprogression, hypothesized to be a drug-induced acceleration of the tumor burden. Despite it being >10 years since the first immune-oncology drug was approved, neither the biology behind these paradoxical responses has been well understood, nor their incidence, identification criteria, predictive biomarkers, or clinical impact have been fully described. Immune-based Response Evaluation Criteria in Solid Tumors (iRECIST) guidelines have been published as a revision to the RECIST V.1.1 criteria for use in trials of immunotherapeutics, and the iRECIST subcommittee (of the RECIST Working Group) is working on elucidating these aspects, with data sharing a current major challenge to move forward with this unmet need in immuno-oncology.
There are limited clinical data comparing extended dosing (ED) versus standard dosing (SD) of pembrolizumab for metastatic non-small-cell lung cancer.
This retrospective study included patients with ...metastatic non-small-cell lung cancer and PD-L1 tumor proportion score ≥50% treated with one or more cycles of single-agent pembrolizumab with SD or ED from January 2018 to December 2020.
A higher proportion of patients were alive in the ED group (vs SD) at 6 months (94 vs 51%), 12 months (94 vs 33%) and data cutoff (94 vs 26%) (p < 0.001 for all). The rate (44 vs 32%; p = 0.407) and severity of grade ≥3 immune-related adverse events were similar (50 vs 52%); however, ED patients more frequently discontinued treatment due to toxicity (45 vs 15%; p < 0.001).
A greater proportion of ED patients were alive at data cutoff, and the rate and severity of immune-related adverse events were similar between groups.
Multiple non-redundant immunosuppressive pathways are active within the microenvironment of cancers to avoid tumor eradication by the immune system. Our results demonstrate that the CD73-adenosine ...pathway is a major immunosuppressive mechanism co-opted by ovarian tumors to escape antitumor immunity. In ovarian cancer patients, high CD73 expression correlates with poor outcome and impaired CD8
+
T cell immunosurveillance.
The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms ...underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade.
Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73).
NCT was associated with increased infiltration of cytotoxic CD8+ T cells and CD20+ B cells. Moreover, NCT was associated with increases in CD8+CD103+ and CD4+CD103+PD-1+TIM3− tissue resident memory T cells. Gene expression profiling supported memory function of CD8+ and CD4+ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery.
Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8+ and CD4+ memory helper T cells.
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