Schematic representation of co-mutation-associated changes in the immune
and non-immune microenvironment of KRAS-mutant lung
adenocarcinoma (LUAD). (a) LKB1 inactivation promotes
epigenetic suppression of STING and insensitivity to cytosolic
DNA that accumulates in the cytoplasm of KRAS- and
LKB1-mutant (KL) cells due to dysfunctional
mitochondria136. KL
tumors are further characterized by a pro-inflammatory cytokine milieu with
accumulation of immunosuppressive neutrophils, marked paucity of CD4+ and CD8+
T-cells and evidence of T-cell exhaustion68, 135. The
potential contributions of immune cell metabolic restriction, altered
angiogenesis and acidification of the tumor microenvironment (highlighted in
blue) to the immune-inert phenotype of KL tumors remain as yet unexplored, but
represent plausible directions for future study. (b) MYC fosters immune evasion
of murine KrasG12D- driven LUADs through IL-23-
mediated expulsion of T, B and NK cells and CCL9-mediated macrophage recruitment
and secretion of immunosuppressive VEGF138. (c) KEAP1 mutations, which
frequently co-occur with mutations in LKB1, particularly in the
context of KRAS-mutant LUAD, have also been associated with low
intra-tumoral density of infiltrating T- and B- lymphocytes, although the
possible role of KEAP1 loss on NK cell infiltration remains
unclear141.
Stabilization of NRF2 as a result of KEAP1 inactivation may further promote
reduced expression of STING through post-transcriptional regulation142. (d) Finally, somatic
TP53 mutations have been shown to mediate NF-κB
pathway activation in Kras-mutant murine models of
LUAD146. Although
TP53 mutations have been associated with reduced production
of chemokines required for the recruitment of NK and T cells in some models and
human tumors, in the context of KRAS-mutant LUAD
TP53 co-alterations promote an inflamed tumor immune
microenvironment with increased production of interferon γ (IFNγ)
and increased expression of PD-L1 on the surface of tumor cells67, 68, 186.