Preliminary observations from your clinical trials with cabozantinib are promising, possibly due to the simultaneous targeting of cancer cell signal pathways (RET, MET, AXL), neutrophil function (MET, potentially KIT, and FLT3), and tumor angiogenesis (VEGFR2).52 TAN diversity and recruitment as the cornerstone to understand ICI failure in solid tumors While preexisting adaptive immune response in tumor is required for effective ICI response,44 53 TAN infiltration is predominantly associated with an adverse outcome across all malignancy types53 and these cells present specific features linked with immunosuppression in tumors.10 21 Of note, approaches designed to inhibit neutrophil survival might induce a compensatory neutrophil production in bone marrow, leading to the release of young neutrophils in the circulation, as our recent experiments in C56BL/6J mice treated with an anti-Ly6G antibody exhibited.25 54 These newly generated neutrophils might develop opposite functions Flupirtine maleate compared with those of mature neutrophils present in non-treated mice.55 Therefore, although neutrophil involvement seems obvious, it is often difficult to determine whether the observed biological effects are due to neutrophil number reduction (depletion) or increased renewal Flupirtine maleate in tissues (turnover).25 54 Furthermore, association between neutrophils and response to ICIs is not restricted to the TME. TANs play an important role in resistance to antiangiogenic drugs reducing their clinical benefit when used in combination with ICIs. Finally, exploring the clinical/translational aspects of neutrophil impact on the response to ICIs offers the opportunity to propose new translational research avenues to better understand TAN biology and treat patients. is usually associated with higher tumor-promoting TAN recruitment and immune checkpoint blockade resistance in lung malignancy.44 45 The PTEN signaling pathway is also a great example of oncogenic pathway that links ICI resistance to TAN recruitment. In malignancy cells, loss of PTEN is usually associated with phosphatidylinositol-3-kinase (PI3K)-AKT signaling overactivation that drives the expression of immunosuppressive cytokines, lowering T-cell recruitment, and enhancing TAN accumulation in the tumor mass.46 47 Therefore, PI3K/ inhibitors (duvelisib and GSK2636771) that target PTEN mutated cancer cells might also remodel the TME.47 48 Furthermore, the MET inhibitor capmatinib increases ICI efficacy in various solid cancer mouse models through alteration of neutrophil recruitment at sites with T cell-induced inflammation.49 A phase II clinical trial (“type”:”clinical-trial”,”attrs”:”text”:”NCT04139317″,”term_id”:”NCT04139317″NCT04139317) is currently testing the efficacy of pembrolizumab in NSCLC combined or not with capmatinib, irrespectively of the cancer MET mutation status. Finally, clinical innovations may come from cabozantinib, a MET, RET, AXL, VEGFR2, FLT3, and KIT inhibitor that reprograms TANs toward antitumor activity.50 51 There are currently Flupirtine maleate 48 and 47 ongoing clinical trials in which the pan-TKI cabozantinib is combined with PD-1/PD-L1 or CTLA-4 blockade, respectively. Preliminary observations from your clinical trials with cabozantinib are encouraging, possibly due to the simultaneous targeting of malignancy cell transmission pathways (RET, MET, AXL), neutrophil function (MET, potentially KIT, and FLT3), and tumor angiogenesis (VEGFR2).52 TAN diversity and recruitment as the cornerstone to understand ICI failure in sound tumors While preexisting adaptive immune response in tumor is required for effective ICI response,44 53 TAN infiltration is predominantly associated with an adverse end result across all malignancy types53 and these cells present specific features linked with immunosuppression in tumors.10 21 Of note, approaches designed to inhibit neutrophil survival might induce a compensatory neutrophil production in bone marrow, leading to the release of young neutrophils in the circulation, as our recent experiments in C56BL/6J mice treated with an anti-Ly6G antibody exhibited.25 54 These newly generated neutrophils might develop opposite functions compared with those of mature neutrophils present in non-treated mice.55 Therefore, although neutrophil involvement seems obvious, it is often difficult to determine whether the observed biological effects are due to neutrophil number reduction (depletion) or increased renewal in tissues (turnover).25 54 Furthermore, association between neutrophils and response to ICIs is not restricted to the TME. Indeed, an alteration of neutrophil biogenesis and survival as reflected by an elevated absolute neutrophil count (ANC) in peripheral blood and an increased in the neutrophil-to-lymphocyte ratio (NLR) predicts the response to ICIs across multiple malignancy types.56 57 Neutrophil diversity in patients with cancer TAN phenotypic diversity in cancer was formally demonstrated by single-cell transcriptomic analysis in samples from patients with lung cancer and from KrasLSLG12D/WT; p53fl/fl (KP) mice with lung malignancy.58 This study identified five populations of neutrophils in human tumors and six in mouse lung adenocarcinoma, and also six neutrophil clusters in blood samples from patients.58 Particularly, this analysis showed the existence of a subpopulation of human TANs characterized by the expression of peptidase inhibitor 3 (PI3).58 This cell subpopulation displays a similar transcriptional profile as the SiglecF+ tumor-promoting TANs identified earlier in KP mice.59 Interestingly, this tumor-specific neutrophil cluster recognized in mouse lung tumor is also characterized by elevated expression of LOX1/ em OLR1 /em , a potential marker of human LDN in peripheral blood of patients with cancer.60 Hence, similarity and differences between mouse and human tumor-promoting TANs remains to be clarified however Vegfb the observation listed above suggest that both mice and human tumor promoting TANs might share, at least partially, comparable transcriptomic identity and origin. While immunosuppressive TAN and circulating neutrophils (frequently named PMN-MDSC or G-MDSC) are suspected to originate from immature neutrophils,7 in KP mice, tumor-promoting SiglecF+ TANs.