A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments

Therapeutic success of targeted therapy with BRAF inhibitors (BRAFi) for melanoma is limited by resistance development. Observations from preclinical mouse models and recent insights into the immunological effects caused by BRAFi give promise for future development of combination therapy for human melanoma. In our study, we used the transplantable D4M melanoma mouse model with the BRAFV600E mutation and concomitant PTEN loss in order to characterize alterations in tumor‐infiltrating effector immune cells when tumors become resistant to BRAFi. We found that BRAFi‐sensitive tumors displayed a pronounced inflammatory milieu characterized by high levels of cytokines and chemokines accompanied by an infiltration of T and NK cells. The tumor‐infiltrating effector cells were activated and produced high levels of IFN‐γ, TNF‐α and granzyme B. When tumors became resistant and progressively grew, they reverted to a low immunogenic state similar to untreated tumors as reflected by low mRNA levels of proinflammatory cytokines and chemokines and fewer tumor‐infiltrating T and NK cells. Moreover, these T and NK cells were functionally impaired in comparison to their counterparts in BRAFi‐sensitive tumors. Their effector cell function could be restored by additional peritumoral treatment with the TLR7 agonist imiquimod, a clinically approved agent for nonmelanoma skin cancer. Indeed, resistance to BRAFi therapy was delayed and accompanied by high numbers of activated T and NK cells in tumors. Thus, combining BRAFi with an immune stimulating agent such as a TLR ligand could be a promising alternative approach for the treatment of melanoma.

Section: Discussionmentioning

confidence: 99%

A TLR7 agonist strengthens T and NK cell function during BRAF‐targeted therapy in a preclinical melanoma model

Bellmann

Cappellano

Schachtl-Rieß

et al. 2019

“…34 In the present analysis, we found that intratumoural delivery of oxaliplatin caused FLT3LG release into the circulation, supporting the notion that oxaliplatin may promote an intratumoural immune response that specifically recruits dendritic cells to present antigens released by the dying tumour cells to cytotoxic lymphocytes, ultimately providing systemic immunity. 36 However, genuine cure of the metastatic disease was additionally contingent on therapeutic conversion to resectability as a result of the 'classic' cytotoxic effect of chemotherapy. 36 However, genuine cure of the metastatic disease was additionally contingent on therapeutic conversion to resectability as a result of the 'classic' cytotoxic effect of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Patients who experienced a pronounced rise in serum levels of the fms-related tyrosine kinase 3 ligand (FLT3LG) during the neoadjuvant treatment course, interpreted as ICD induction, had significantly better progression-free survival than those without such response, implying that an advantageous systemic immune response might have been invoked by oxaliplatin. 36 Because FLT3LG in the systemic circulation may reflect an immune response generated within the tumour microenvironment, we hypothesised it may be used in the context of predicting long-term outcome of first-line oxaliplatin-HAI in patients with primarily unresectable CLM. 35 In melanoma, which is the archetype immunogenic tumour entity, it was recently demonstrated that intratumoural natural killer cells are the source of the dendritic cell-stimulatory FLT3LG.…”

Section: Introductionmentioning

confidence: 99%

Antitumour immunity invoked by hepatic arterial infusion of first‐line oxaliplatin predicts durable colorectal cancer control after liver metastasis ablation: 8–12 years of follow‐up

Abrahamsson

Jensen

Berven

et al. 2020

In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.Additional Supporting Information may be found in the online version of this article.

“…Because DC1s are very rare in tumors, they have not been investigated in humans in as much detail as they have been in mice . Therefore, recent studies have developed a gene expression signature to represent the level of DC1s . By analyzing these DC1‐related signatures in tumor tissue from breast cancer patients, we showed positive correlations among the rs1024176 genotype, XCL1 expression, the DC1 signature and breast cancer survival, highlighting the importance of immune control in breast cancer progression.…”

Section: Discussionmentioning

confidence: 94%

“…To achieve this, conventional DC1s are attracted to the tumor microenvironment, where they present tumor antigens, migrate into tumor‐draining lymph nodes to activate CD8 + T cells and trigger antitumor immunity to enhance patient survival. To examine whether DC1s have infiltrated tumor tissues, recent studies have used the expression of a set of genes as a DC1 signature to indicate DC1 accumulation in human tissue . Hence, we followed the same approach, using these well‐defined DC1 signatures, including conventional DC1 (cDC1), stimulatory DC (SDC) and newly defined DC1 (nDC1) signatures, to explore the consequence of the A allele of rs1024176.…”

Section: Resultsmentioning

confidence: 99%

A functional variant near XCL1 gene improves breast cancer survival via promoting cancer immunity

Chou

Hsiung

Chen

et al. 2020

Most genome‐wide association studies (GWASs) identify genetic variants for breast cancer occurrence. In contrast, few are for recurrence and mortality. We conducted a GWAS on breast cancer survival after diagnosis in estrogen receptor‐positive patients, including 953 Taiwanese patients with 159 events. Through Cox proportional hazard models estimation, we identified 24 risk SNPs with p < 1 × 10−5. Based on imputation and integrated analysis, one SNP, rs1024176 (located in 1q24.2, p = 2.43 × 10−5) was found to be a functional variant associated with breast cancer survival and XCL1 gene expression. A series of experimental approaches, including cell‐based analyses and CRISPR/Cas9 genome‐editing system, were then used and identified the transcription factor MYBL2 was able to discriminately bind to the A allele of rs1024176, the protective variant for breast cancer survival, which promoted XCL1 expression, but not to the G allele of rs1024176. The chemokine XCL1 attracts type 1 dendritic cells (DC1s) to the tumor microenvironment. In breast cancer tissues, we applied a two‐step Mendelian randomization analysis, using expression quantitative trait loci as instrumental variables, to confirm higher XCL1 expression was correlated with higher DC1 signatures and favorable disease progression, through the causal effect of rs1024176‐A allele. Our study supports the genetic effect on preventing breast cancer survival through XCL1‐induced DC1 recruitment in tumor microenvironment.