Spatial multiplex analysis of lung cancer reveals that regulatory T cells attenuate KRAS-G12C inhibitor-induced immune responses.

Kirsten rat sarcoma virus (KRAS)-G12C inhibition causes remodeling of the lung tumor immune microenvironment and synergistic responses to anti-PD-1 treatment, but only in T cell infiltrated tumors. To investigate mechanisms that restrain combination immunotherapy sensitivity in immune-excluded tumors, we used imaging mass cytometry to explore cellular distribution in an immune-evasive KRAS mutant lung cancer model. Cellular spatial pattern characterization revealed a community where CD4 and CD8 T cells and dendritic cells were gathered, suggesting localized T cell activation.

Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade.

Mutant selective drugs targeting the inactive, GDP-bound form of KRAS have been approved for use in lung cancer, but resistance develops rapidly. Here we use an inhibitor, (RMC-4998) that targets RAS in its active, GTP-bound form, to treat KRAS mutant lung cancer in various immune competent mouse models. RAS pathway reactivation after RMC-4998 treatment could be delayed using combined treatment with a SHP2 inhibitor, which not only impacts tumour cell RAS signalling but also remodels the tumour microenvironment to be less immunosuppressive.

CRISPR-Cas9 Screening Identifies KRAS-Induced COX2 as a Driver of Immunotherapy Resistance in Lung Cancer.

Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identified mechanisms by which oncogenic KRAS promotes immune evasion, most notably via upregulation of immunosuppressive COX2 in cancer cells.

CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes.

A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport.

An Immunogenic Model of KRAS-Mutant Lung Cancer Enables Evaluation of Targeted Therapy and Immunotherapy Combinations.

Unlabelled: Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies.

Therapeutic KRAS inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers.

Recently developed KRAS inhibitory drugs are beneficial to lung cancer patients harboring KRAS mutations, but drug resistance frequently develops. Because of the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, these drugs can indirectly affect antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterized how KRAS inhibition reverses immunosuppression driven by oncogenic KRAS in a number of preclinical lung cancer models with varying levels of immunogenicity.

Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry.

Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy.

Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer.

KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated protein kinase kinase (MEK) and insulin-like growth factor 1 receptor (IGF1R) signaling. Here, we show that this effect is markedly enhanced by simultaneous inhibition of mammalian target of rapamycin (mTOR) while maintaining selectivity for the KRAS-mutant genotype.

GLP-1 nanomedicine alleviates gut inflammation.

The gut hormone, glucagon like peptide-1 (GLP-1) exerts anti-inflammatory effects. However, its clinical use is limited by its short half-life. Previously, we have shown that GLP-1 as a nanomedicine (GLP-1 in sterically stabilized phospholipid micelles, GLP-1-SSM) has increased in vivo stability.