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With regards to serum, our results are in accordance with previous studies showing a fair predominance of serum-susceptible strains in CF patients30,32,79,80,81,82. The loss of O-antigen typically found on CF isolates (rendering non-typeable strains often reported to be serum-susceptible) is also in accordance with our results: 19 of our 24 CF isolates were non-typeable. But, precisely because of this we perhaps expected an overall higher degree of susceptibility in our CF isolates [less than the half could be considered susceptible (survival below 1%)], and even a trend to increased susceptibility when comparing early with late CF isolates. Nevertheless, some works have demonstrated that the existence of non-typeable strains (lacking O-antigen) proceeding from CF patients and showing serum-resistance was not that exceptional83,84. These studies also proved that the typeable isolates are not necessarily serum-resistant, features that some of our strains display. Moreover, the observation of a trend using two isolates (early-late) does not always ensure covering the necessary time lapse to visualize the selection of a certain phenotype. This is what may have happened with some of our CF isolates. This hypothesis has been previously suggested in other works dealing with additional adaptations during the CF process27. Thus, our results suggest questioning the classic conception of CF-proceeding strains being almost uniformly susceptible to serum32,79,80,81,82. In any case, as could be argued for the rest of treatments and phenotypes, the particularities of CF lung (poor diffusion of complement compounds and/or reduced level of immune activation enabled by the biofilm lifestyle and/or by the loss of O-chains, etc.) have been proposed to allow the selection of complement-susceptible phenotypes in exchange for other benefits achieved through adaptive mutations81,85,86,87. Otherwise, the need for LPS-linked resistance to killing and opsonization by complement to survive within the bloodstream88,89,90 has been highlighted, which obviously supports the results of high resistance of our bacteremia strains.

In summary, at concentrations delivering selective PI3Kγ inhibition AZD3458 efficacy in the MC38 model is achieved without depleting macrophages, instead it influences the activation status across the different subsets of tumor-associated macrophages consistent with a cytotoxic/killing MHCIIhi/iNOS+ profile and also increases infiltrating antigen-presenting DCs. The changes in the antigen-presenting myeloid cells are followed by activation of CD8+ T-cell phenotype resulting in immune-mediated antitumor response (Supplementary Fig. S7).

The potential heterogeneity is exemplified by the impact of AZD3458 on MC38 tumors. MC38 exhibit an immune-infiltrated TME with defined macrophage populations (44), and partial sensitivity to ICB (29, 30). Despite antitumor activity being similar to CT-26 and 4T1, AZ3458 did not deplete macrophages in MC38. Although tumor macrophages increased immune activation pathways a mixed profile of differentiation biomarkers was observed, suggesting enhanced efficacy without influencing the classical immunosuppressive polarization phenotype (M1/M2). AZD3458 treatment also increased DC infiltration and activation, which in conjunction with macrophages displaying antigen-presenting and -killing phenotype will help optimize antitumor response directly or by increasing effector T-cell activation. Therefore, although PI3Kγ inhibition may reduce tumor macrophages in some settings (9), depletion or repolarization is not essential as increased antigen presentation and cytotoxic potential within the TME can improve efficacy. AZD3458 also modulated neutrophil activation and recruitment, which also influence response to ICB (45). How PI3Kγ inhibitors influence tumor neutrophil function, and whether this contributes to efficacy remains to be established.

In summary, we show that the PI3Kγ inhibitor AZD3458 can enhance checkpoint efficacy associated with modulation of tumor macrophage production of anti-inflammatory cytokines, increase in pro-inflammatory signaling and activated bacterial-like macrophage killing profile. In parallel activation of DCs is evident. Collectively, this enhances CD8 Teff cell activation and immune-mediated efficacy. Importantly, these data suggest that the effects of inhibiting PI3Kγ in the TME will vary based on context. Rather than simply depleting or repolarizing immunosuppressive macrophages, the effects may be more heterogeneous, and moreover impact other programming events such as the metabolic features, induction of cytotoxic functions, and antigen presentation potential. This has important implications for both biomarker selection and interpretation, as well as for optimization of treatment regimens.

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