Efficacy Of Immune Checkpoint Blockade Research Articles

Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.

Immune checkpoint blockade (ICB) therapies have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, sex-specific differences in response to ICB have been observed, with males receiving a greater benefit from ICB than females, although the mechanism or mechanisms underlying this difference are unknown. Mining published transcriptomic data sets, we determined that the response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor α (ERα) stimulated melanoma growth in murine models by skewing macrophage polarization toward an immune-suppressive state that promoted CD8+ T cell dysfunction and exhaustion and ICB resistance. This activity was not evident in mice harboring macrophage-specific depletion of ERα, confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD), decreased tumor growth, stimulated adaptive immunity, and increased the antitumor efficacy of ICBs. Further, a gene signature that determines ER activity in macrophages predicted survival in patients with melanoma treated with ICB. These results highlight the importance of E2/ER signaling as a regulator of intratumoral macrophage polarization, an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.

The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage

High expression of programmed death-ligand 1 (PD-L1) in cancer cells drives immune-independent, cell-intrinsic functions, leading to resistance to DNA-damaging therapies. We find that high expression of the ubiquitin E3 ligase FBXO22 sensitizes nonsmall cell lung cancer (NSCLC) cells to ionizing radiation (IR) and cisplatin, and that activation of FBXO22 by phosphorylation is necessary for this function. Importantly, FBXO22 activates PD-L1 ubiquitination and degradation, which in turn increases the sensitivity of NSCLC cells to DNA damage. Cyclin-dependent kinase 5 (CDK5), aberrantly active in cancer cells, plays a crucial role in increasing the expression of PD-L1 in medulloblastoma [R. D. Dorand etal, Science 353, 399-403 (2016)]. We show in NSCLC cells that inhibiting CDK5 or reducing its expression increases the level of FBXO22, decreases that of PD-L1, and increases the sensitivity of the cells to DNA damage. We conclude that FBXO22 is a substrate of CDK5, and that inhibiting CDK5 reduces PD-L1 indirectly by increasing FBXO22. Pairing inhibitors of CDK5 with immune checkpoint inhibitors may increase the efficacy of immune checkpoint blockade alone or in combination with DNA-damaging therapies.

Mutations in DNA damage response pathways as a potential biomarker for immune checkpoint blockade efficacy: evidence from a seven-cancer immunotherapy cohort.

Recently several studies have demonstrated the implications of mutations in DNA damage response (DDR) pathways for immune checkpoint blockade (ICB) treatment. However, smaller sample sizes, lesser cancer types, and the lack of multivariate-adjusted analyses may produce unreliable results. From the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort, we curated 1363 ICB-treated patients to evaluate the association of DDR mutations with immunotherapy prognosis. Besides, 4286 ICB-treated-naive patients from the Cancer Genome Atlas (TCGA) cohort were used to explore the intrinsic prognosis of DDR mutations. Factors in the microenvironment regarding DDR mutations were also assessed. We found that patients with DDR mutations exhibited a significantly prolonged immunotherapy overall survival via multivariate Cox model in the MSKCC cohort (HR: 0.70, P < 0.001). Specific cancer analyses revealed that patients with DDR mutations could obtain the better ICB prognosis in bladder cancer and colorectal cancer (HR: 0.59 [P = 0.034] and 0.33 [P = 0.006]). Stratified analyses showed that age >60, male gender, high mutation burden, and PD-1/PD-L1 treatment were the positive conditions for ICB survival benefits of DDR mutations (all P < 0.01). Mutations of 4 DDR genes, including MRE11A, MSH2, ATM, and POLE could predict favorable ICB prognoses (all P < 0.01). A better immune microenvironment was observed in DDR mutated patients. Mutations in DDR pathways or single DDR genes were associated with preferable ICB efficacy in specific cancers or subpopulations. Findings from our study would provide clues for tailing clinical trials and immunotherapy strategies.

Improved prediction of immune checkpoint blockade efficacy across multiple cancer types.

Only a fraction of patients with cancer respond to immune checkpoint blockade (ICB) treatment, but current decision-making procedures have limited accuracy. In this study, we developed a machine learning model to predict ICB response by integrating genomic, molecular, demographic and clinical data from a comprehensively curated cohort (MSK-IMPACT) with 1,479 patients treated with ICB across 16 different cancer types. In a retrospective analysis, the model achieved high sensitivity and specificity in predicting clinical response to immunotherapy and predicted both overall survival and progression-free survival in the test data across different cancer types. Our model significantly outperformed predictions based on tumor mutational burden, which was recently approved by the U.S. Food and Drug Administration for this purpose1. Additionally, the model provides quantitative assessments of the model features that are most salient for the predictions. We anticipate that this approach will substantially improve clinical decision-making in immunotherapy and inform future interventions.

CONFIRMing single-drug immune checkpoint blockade efficacy in mesothelioma

Mesothelioma is an uncommon cancer, but, despite a reduction in asbestos use in high-income countries in the past few decades, we are still facing a global epidemic of this disease. Immune checkpoint blockade had an inauspicious start in mesothelioma, when the anti-CTLA-4 antibody, tremelimumab, was shown to not improve overall survival compared with placebo in the second-line setting. 1 Maio M Scherpereel A Calabro L et al. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol. 2017; 18: 1261-1273 Summary Full Text Full Text PDF PubMed Scopus (271) Google Scholar However, outcomes from several subsequent single-arm clinical trials suggested anti-tumour activity of PD-1 or PD-L1 blockade in patients with mesothelioma. 2 Alley EW Lopez J Santoro A et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2017; 18: 623-630 Summary Full Text Full Text PDF PubMed Scopus (335) Google Scholar , 3 Quispel-Janssen J van der Noort V de Vries JF et al. Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma. J Thorac Oncol. 2018; 13: 1569-1576 Summary Full Text Full Text PDF PubMed Scopus (150) Google Scholar , 4 Okada M Kijima T Aoe K et al. Clinical efficacy and safety of nivolumab: results of a multicenter, open-label, single-arm, Japanese phase II study in malignant pleural mesothelioma (MERIT). Clin Cancer Res. 2019; 25: 5485-5492 Crossref PubMed Scopus (138) Google Scholar Objective tumour response rates ranged from 20–30%. Together with promising progression-free survival and overall survival outcomes, these trials triggered inclusion of single drug PD-1 inhibition as an option for subsequent-line therapy in some—but not all—clinical practice guidelines from as early as 2017. Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trialNivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy. Full-Text PDF Open Access

Potential Biomarkers for the Efficacy of PD-1-PD-L Blockade in Cancer.

A decade ago, immune checkpoint blockade emerged as a major breakthrough in oncology, proposing a novel approach by which immune brakes could be released to enhance antitumor responses. Despite apparently modest improvement of the median duration of response, a spectacular doubling of long-term responses as compared to the available standard of care was seen, for instance, in metastatic melanoma. It soon became obvious that the percentage of patients responding to these novel approaches is relatively small, and the importance of an accurate prediction of responders became more and more clear. Strong predictive markers would allow for the administration of immune checkpoint blocker therapy to the patients most likely to benefit from it, and sparing the potential non-responders of a treatment which is far from innocuous, being associated with significant side-effects and, not least, an important price tag. A number of potential response predictors have already been investigated and partly validated, but they do not cover the major unmet need encountered in the current clinical setting. Here, we review biomarkers for immune checkpoint blockade efficacy, either clinically validated and currently in use, or which have been proposed as candidates and are currently under investigation.

Peptide hydrogels loaded with irradiated tumor cell secretions enhance cancer immunotherapy

In advanced stage patients, traditional cancer chemotherapies often demonstrate limited tumor growth inhibition and fail to elicit sufficient anti-tumor immunity required for long-lasting responses. Herein, we developed a therapeutic peptide hydrogel manufactured using a PEG cross-linked melittin-peptide scaffold that not only itself induces tumor cell killing, but also encapsulates the processed cell secretions of autologous, irradiated tumor cells. MLT-RADA-Polyethylene glycol (MRP) loaded with the concentrated ultrafiltration (UF) retentate from irradiated tumor cell media, denoted as UF@MRP effectively reshapes the tumor microenvironment (TME) by stimulating dendritic cell maturation and reprogramming macrophages toward a tumoricidal M1 phenotype. In multiple murine tumor models, in which immune checkpoint blockade (ICB) alone did not control advanced disease, intratumoral administration of UF@MRP enhanced ICB efficacy, leading to prolonged survival. The combination of UF@MRP and ICB appears to be an effective approach to rapidly kill tumor cells, diminish immunosuppression in the TME, and activate host adaptive immune responses, all of which work in concert in an immunotherapy regime to control established and aggressive tumors.

Identification of an Autophagy-Related Risk Signature Correlates With Immunophenotype and Predicts Immune Checkpoint Blockade Efficacy of Neuroblastoma.

Neuroblastoma is one of the malignant solid tumors with the highest mortality in childhood. Targeted immunotherapy still cannot achieve satisfactory results due to heterogeneity and tolerance. Exploring markers related to prognosis and evaluating the immune microenvironment remain the major obstacles. Herein, we constructed an autophagy-related gene (ATG) risk model by multivariate Cox regression and least absolute shrinkage and selection operator regression, and identified four prognostic ATGs (BIRC5, GRID2, HK2, and RNASEL) in the training cohort, then verified the signature in the internal and external validation cohorts. BIRC5 and HK2 showed higher expression in MYCN amplified cell lines and tumor tissues consistently, whereas GRID2 and RNASEL showed the opposite trends. The correlation between the signature and clinicopathological parameters was further analyzed and showing consistency. A prognostic nomogram using risk score, International Neuroblastoma Staging System stage, age, and MYCN status was built subsequently, and the area under curves, net reclassification improvement, and integrated discrimination improvement showed more satisfactory prognostic predicting performance. The ATG prognostic signature itself can significantly divide patients with neuroblastoma into high- and low-risk groups; differentially expressed genes between the two groups were enriched in autophagy-related behaviors and immune cell reactions in gene set enrichment analysis (false discovery rate q -value < 0.05). Furthermore, we evaluated the relationship of the signature risk score with immune cell infiltration and the cancer-immunity cycle. The low-risk group was characterized by more abundant expression of chemokines and higher immune checkpoints (PDL1, PD1, CTLA-4, and IDO1). The risk score was significantly correlated with the proportions of CD8+ T cells, CD4+ memory resting T cells, follicular helper T cells, memory B cells, plasma cells, and M2 macrophages in tumor tissues. In conclusion, we developed and validated an autophagy-related signature that can accurately predict the prognosis, which might be meaningful to understand the immune microenvironment and guide immune checkpoint blockade.

Super-enhancer receives signals from the extracellular matrix to induce PD-L1-mediated immune evasion via integrin/BRAF/TAK1/ERK/ETV4 signaling.

Objective:PD-L1 and PD-L2 expression levels determine immune evasion and the therapeutic efficacy of immune checkpoint blockade. The factors that drive inducible PD-L1 expression have been extensively studied, but mechanisms that result in constitutive PD-L1 expression in cancer cells are largely unknown.Methods:DNA elements were deleted in cells by CRISPR/Cas9-mediated knockout. Protein function was inhibited by chemical inhibitors. Protein levels were examined by Western blot, mRNA levels were examined by real-time RT-PCR, and surface protein expression was determined by cellular immunofluorescence and flow cytometry. Immune evasion was examined by in vitro T cell-mediated killing.Results:We determined the core regions (chr9: 5, 496, 378–5, 499, 663) of a previously identified PD-L1L2-super-enhancer (SE). Through systematic analysis, we found that the E26 transformation-specific (ETS) variant transcription factor (ETV4) bound to this core DNA region but not to DNA surrounding PD-L1L2SE. Genetic knockout of ETV4 dramatically reduced the expressions of both PD-L1 and PD-L2. ETV4 transcription was dependent on ERK activation, and BRAF/TAK1-induced ERK activation was dependent on extracellular signaling from αvβ3 integrin, which profoundly affected ETV4 transcription and PD-L1/L2 expression. Genetic silencing or pharmacological inhibition of components of the PD-L1L2-SE-associated pathway rendered cancer cells susceptible to T cell-mediated killing.Conclusions:We identified a pathway originating from the extracellular matrix that signaled via integrin/BRAF/TAK1/ERK/ETV4 to PD-L1L2-SE to induce PD-L1-mediated immune evasion. These results provided new insights into PD-L1L2-SE activation and pathways associated with immune checkpoint regulation in cancer.

Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment

The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.

Can gut microbes predict efficacy and toxicity of combined immune checkpoint blockade?

A recent report in Nature Medicine pinpoints a role for gut microbiota in response and toxicity to combined immune checkpoint blockade targeting CTLA-4 and PD-1. This emergent study provides insights that can be used to leverage microbiota in the design of anticancer therapies to mitigate toxicity while enhancing efficacy.

In This Issue

In This Issue

Sharpening up tumor microenvironment to enhance the efficacy of immune checkpoint blockade on head and neck cancer using a CpG-oligodeoxynucleotide

Head and neck cancers are a type of life-threatening cancers characterized by an immunosuppressive tumor microenvironment. Only less than 20% of the patients respond to immune checkpoint blockade therapy, indicating the need for a strategy to increase the efficacy of immunotherapy for this type of cancers. Previously, we identified a type B CpG-oligodeoxynucleotide (CpG-ODN) called CpG-2722, which has the universal activity of eliciting an immune response in grouper, mouse, and human cells. In this study, we further characterized and compared its cytokine-inducing profiles with different types of CpG-ODNs. The antitumor effect of CpG-2722 was further investigated alone and in combination with an immune checkpoint inhibitor in a newly developed syngeneic orthotopic head and neck cancer animal model. Along with other inflammatory cytokines, CpG-2722 induces the gene expressions of interleukin-12 and different types of interferons, which are critical for the antitumor response. Both CpG-2722 and anti-programmed death (PD)-1 alone suppressed tumor growth. Their tumor suppression efficacies were further enhanced when CpG-2722 and anti-PD-1 were used in combination. Mechanistically, CpG-2722 shaped a tumor microenvironment that is favorable for the action of anti-PD-1, which included promoting the expression of different cytokines such as IL-12, IFN-β, and IFN-γ, and increasing the presence of plasmacytoid dendritic cells, M1 macrophages, and CD8 positive T cells. Overall, CpG-2722 provided a priming effect for CD8 positive T cells by sharpening the tumor microenvironment, whereas anti-PD-1 released the brake for their tumor-killing effect, resulting in an enhanced efficacy of the combined CpG-2722 and anti-PD-1.

In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target

Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled invivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebpδ protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpδ to suppress expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy in TNBC by regulating chemokine secretion and macrophage infiltration in the tumor microenvironment.

Checkpoint Blockade + Chemotherapy: the Right Combination for AML?

An emerging strategy to enhance the efficacy of immune checkpoint blockade in relapsed/refractory cancers is increasing immunogenic cell death via combination with cytotoxic therapies. Understanding the effects of cytotoxic and immunotherapeutic agents on immune cell populations will enable improved mechanism-based design of combination therapies to maximum efficacy and minimum toxicity.See related article by Zeidner et al., p. 616.

KAT2B is an immune infiltration-associated biomarker predicting prognosis and response to immunotherapy in non-small cell lung cancer.

Over the past few years, dramatic breakthroughs in the field of tumor immunotherapy with immune checkpoint inhibitors (ICIs) have made a therapeutic revolution for non-small cell lung cancer (NSCLC). While only some patients present a favorable response to this treatment. It is urgent to explore the potential molecular mechanisms underlying the regulation of tumor immune microenvironment in the process of immunotherapy. Lysine acetyltransferase 2B (KAT2B) plays a crucial role in the regulation of gene expression at the post-transcriptional level by acetylation, and is associated with many types of cancer. RNA-sequencing data,genetic mutation data,and corresponding clinical information were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, then subjected to immune characteristics, gene expression, survival, genetic alteration, enrichment analyses. KAT2B expression correlated positively with infiltrating levels of multiple immune cells and mRNA expression levels of immune checkpoint genes in NSCLC. Furthermore, KAT2B expressionwas downregulated in tumor tissues, and low KAT2B expression was associated with unsatisfactory efficacy of immune checkpoint blockade (ICB) and poor prognosis of patients with lung adenocarcinoma. Moreover, there were higher somatic genes mutation frequency in patients with low expression of KAT2B. Finally, functional enrichment analysis suggested that KAT2B was mainly linked to the regulation of immune cells and interferon - gamma (IFN-γ) mediated signaling pathways, response to IFN-γ, antigen processing and presentation. This is the first comprehensive study to disclose that KAT2B is correlated with immune infiltrates and may serve as a novel biomarker predicting prognosis and response to immunotherapy in NSCLC.

KS01.4.A NK cells as key orchestrators in mediating the anti-tumour response to immune checkpoint blockade in melanoma brain metastases

Abstract BACKGROUND Brain metastases (BrM) are an unmet clinical need with poor prognosis. 60% of melanoma patients develop BrM. BrM are strongly understudied due to frequent exclusion from clinical trials, and hence treatment options commonly lag behind. Antibodies targeting the immune-inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have demonstrated efficacy against melanoma BrM. Despite this, therapeutic responses are highly variable, and it is unknown why therapy fails in a high proportion of patients. Improved therapeutic strategies require a thorough understanding of potentially exploitable mechanisms of therapeutic efficacy. Our data previously implicated different immune cells, foremost CD8+ T cells, but also NK cells, in the intracranial efficacy and enhanced survival benefit of immune checkpoint blockade (ICB). Our aim here is to investigate the role of NK cells in mediating the response to ICB in melanoma BrM. MATERIAL AND METHODS To study the role of NK cells in the response to ICB in melanoma BrM, a tumour transplantation model of B16 melanoma with simultaneous extracranial (i.e., flank) and brain tumours in C57BL/6 mice was utilised. NK cells were depleted through administration of anti-asialo-GM1 NK cell-depleting antibodies. Confirmation of NK cell depletion and quantification of intratumoral immune cell populations was performed using flow cytometry. Intratumoral gene expression of key chemokines and immune mediator genes was assessed using RT-qPCR and mRNA-seq. RESULTS Highly variable response to ICB with respect to intratumoral accumulation of CD8+ T cells allowed separation of mice into responders and non-responders and revealed genes and pathways associated with response to ICB. NK cell depletion reversed the ICB-mediated increase in the accumulation of CD8+ T cells and significantly reduced the expression of genes associated with response in intracranial and extracranial tumours. The ICB-mediated significant increase in gene expression of various chemokines (i.e., Cxcl9/10) and immune mediators (i.e., Ifng, Prf1 and Gzmb) was significantly abrogated upon NK cell depletion. CONCLUSION NK cells play a critical role in the underlying mechanisms of ICB efficacy through their modulation of the tumour microenvironment and enhancement of CD8+ T cell accumulation in intracranial tumours. Targeting of NK cells may allow potentiation of ICB therapy in the brain, as well as at extracranial sites.

Radiation-activated secretory proteins of Scgb1a1+ club cells increase the efficacy of immune checkpoint blockade in lung cancer.

Radiation therapy (RT) in combination with immune checkpoint inhibitor (ICI) represents a promising regimen for non-small cell lung cancer (NSCLC), however, the underlying mechanisms are poorly characterized. We identified a specific dose of RT that conferred tumor regression and improved survival in NSCLC models when combined with ICI. The immune-modulating functions of RT was ascribed to activated lung-resident Scgb1a1+ club cells. Importantly, mice with club cell-specific knockout of synaptosome-associated protein 23 failed to benefit from the combination treatment, indicating a pivotal role of club cell secretome. We identified 8 club cells secretory proteins, which inhibited immunosuppressive myeloid cells, reduced pro-tumor inflammation, and enhanced anti-tumor immunity. Notably, CC10, a member of club cell secretome was increased in plasma of NSCLC patients responding to the combination therapy. By revealing an immune-regulatory role of club cells, our studies have the potential to guide future clinical trials of ICI in NSCLC.

Mutational burden and immune recognition of gliomas.

Recent evidence suggests high tumor mutational burden (TMB-H) as a predictor of response to immune checkpoint blockade (ICB) in cancer. However, results in TMB-H gliomas have been inconsistent. In this article, we discuss the main pathways leading to TMB-H in glioma and how these might affect immunotherapy response. Recent characterization of TMB-H gliomas showed that 'post-treatment' related to mismatch repair (MMR) deficiency is the most common mechanism leading to TMB-H in gliomas. Unexpectedly, preliminary evidence suggested that benefit with ICB is rare in this population. Contrary to expectations, ICB response was reported in a subset of TMB-H gliomas associated with constitutional MMR or polymerase epsilon (POLE) defects (e.g., constitutional biallelic MMRd deficiency). In other cancers, several trials suggest increased ICB efficacy is critically associated with increased lymphocyte infiltration at baseline which is missing in most gliomas. Further characterization of the immune microenvironment of gliomas is needed to identify biomarkers to select the patients who will benefit from ICB. Intrinsic molecular and immunological differences between gliomas and other cancers might explain the lack of efficacy of ICB in a subset of TMB-H gliomas. Novel combinations and biomarkers are awaited to improve immunotherapy response in these cancers.

Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models.

Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients respond, and sustained remissions are rare. Both chemotherapy and antiangiogenic drugs may improve the efficacy of ICB in mouse tumor models and patients with cancer. Here, we used genetically engineered mouse models of Kras G12D/+;p53 -/- NSCLC, including a mismatch repair-deficient variant (Kras G12D/+;p53 -/-;Msh2 -/-) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, antiangiogenic therapy, and chemotherapy. Antiangiogenic blockade of vascular endothelial growth factor A and angiopoietin-2 markedly slowed progression of autochthonous lung tumors, but contrary to findings in other cancer types, addition of a PD-1 or PD-L1 antibody was not beneficial and even accelerated progression of a fraction of the tumors. We found that antiangiogenic treatment facilitated tumor infiltration by PD-1+ regulatory T cells (Tregs), which were more efficiently targeted by the PD-1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of monocyte origin, which are colony-stimulating factor 1 receptor (CSF1R) dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establish a transforming growth factor-β-rich tumor microenvironment that supported PD-1+ Tregs Dual TAM targeting with a combination of a CSF1R inhibitor and cisplatin abated Tregs, redirected the PD-1 antibody to CD8+ T cells, and improved the efficacy of antiangiogenic immunotherapy, achieving regression of most tumors.