CCRL2 (C-C Motif Chemokine Receptor Like 2)

Meanwhile, MAX449 boosted the therapeutic efficacy of PD-1 antibody in hot and cold tumor model mice. This study provides compelling evidence supporting the clinical evaluation of MAX449 as an innovative therapeutic approach for cancer.

The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs...This agent also suppressed the leukemic growth of TP53- mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53 -mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML.

The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs...In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML. Pyrrolobenzodiazepine(PBD)-conjugated anti-CCRL2 ADC shows anti-leukemic effect in MDS/AML models including TP53 -mutated disease without affecting healthy hematopoietic cells supporting that it is a promising candidate for single-agent or combination therapies in high-risk MDS/AML.

Finally, CCRL2/IFN-γ signaling is associated with the transformation of pre-leukemic single-hit TP53 clones to multi-hit TP53 mutated AML, increased resistance to venetoclax and worse survival in AML. Overall, our findings support that CCRL2 is an essential driver of cell-autonomous IFN-γ signaling response in myeloid neoplasms with erythroid differentiation and TP53 mutations and highlight CCRL2 as a relevant novel target for these neoplasms.

These findings suggest that CCRL2 shapes tumor architecture by rewiring inflammatory signaling networks in a cell-intrinsic manner. Further studies in other cancer types and cell models are needed to determine whether CCRL2's regulatory role is broadly conserved and to explore its potential as a therapeutic target in solid tumors.

Finally, CCRL2/IFN-γ signaling is associated with the transformation of pre-leukemic single-hit TP53 clones to multi-hit TP53 mutated AML, increased resistance to venetoclax and worse survival in AML. Overall, our findings support that CCRL2 is an essential driver of cell-autonomous IFN-γ signaling response in myeloid neoplasms with erythroid differentiation and TP53 mutations and highlight CCRL2 as a relevant novel target for these neoplasms. CCRL2 is overexpressed in AML with loss-of-function TP53 mutations and erythroid differentiation and promotes IFN-γ signaling response via a cell-intrinsic mechanism.

HSF promoted CCRL2 expression and affected M1 polarization via CCRL2, which in turn affected CD8+ T cell-mediated anti-tumor immunity. Our study demonstrated that HSF promoted macrophage M1 polarization and activated CD8+ T cells via CCRL2, thereby inhibiting the progression of LC.

In vivo administration of low doses of 5-Aza induced CCRL2 upregulation, increased recruitment of NK cells, and reduced lung tumor growth. These results identify CCRL2 as an NK-cell lung homing molecule that has the potential to be exploited to promote NK cell-mediated lung immune surveillance.

Overall, these data will elucidate MF gene expression in SOC patients as well as the immunopathogenesis that results in varying presentations. This may facilitate the development of more concise diagnostic criteria and personalized targeted immunotherapies to better health outcomes within a minority population.