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Page 122 Gurule et al. Cancer Drug Resist 2018;1:118-25 I http://dx.doi.org/10.20517/cdr.2018.12

Table 1. Combination therapy trials of TKIs and immunotherapy in lung cancer
Study Identifier Type Oncogene Therapy Status
TATTON NCT02143466 Multi-arm phase EGFR Osimertinib + durvalumab, Recruiting
Ib savolitinib, selumetinib
CheckMate012 NCT01454102 Phase I EGFR Nivolumab+ erlotinib, chemotherapy, Active, not recruiting
ipilimuab
CheckMate370 NCT02574078 Single arm Advanced Nivolumab+ chemo, first line, or SOC Active, not recruiting
NSCLC (ALK) (crizotinib)

immunotherapy exacerbates the frequency and severity of some of the adverse events seen in the clinic,
especially the inflammation-driven toxicities, pneumonitis, hepatitis, and pulmonary fibrosis.

The cellular mechanism responsible for less frequent, but more severe TKI-induced adverse events like liver
failure and ILD is not defined in the literature. We speculate that it may arise from disruption of normal
epithelial tissue homeostasis and an induction of an innate inflammatory response similar to that observed
with EGFR inhibitors in epidermal tissues. In support, studies demonstrate that genetic disruption of MET
in hepatocytes causes an induction of IL6 . Livers from hepatocyte-specific MET knockout mice show
[18]
an increase in immune cell populations including infiltrating neutrophils, macrophages, and cytotoxic T
cells . Inflammatory cytokines also have an established role in hepatocytes, as CXCL10 is found to be
[19]
expressed by hepatocytes isolated from patients with chronic hepatitis C infection and are correlated with
an increase in lobular inflammation and histological severity . Furthermore, the alveolar epithelium is able
[45]
to contribute to the immune landscape of the lung by generating pro-inflammatory cytokines like CXCL10
and CCL2 when stimulated with IFNλ . Studies to investigate the effects of gefitinib on airway repair after
[46]
injury demonstrated that mice treated with gefitinib after naphthalene induced airway injury developed
severe pneumonitis driven primarily by infiltrating neutrophils [47,48] . Bronchial epithelial cells harvested
from these mice demonstrated an increase in proinflammatory genes. Taken together, these studies suggest
that TKIs induce an innate inflammatory immune response in epithelial tissues where their RTK targets
function as dominant signal pathways controlling epithelial homeostasis. Thus, EGFR or MET blockade may
contribute to adverse events like liver toxicities and ILD especially when combined with presently deployed
anti-PD1/PD-L1 agents.

CONCLUSIONS AND PERSPECTIVES
Although induction of clinically graded skin toxicities related to an inflammatory phenotype has been
classified as an adverse event in cancer patients, we propose that this response represents on-target inhibition
of a normal tissue homeostasis program in epithelial cells that is retained in their transformed derivatives.
Importantly, this TKI-induced innate immune response may actually represent a therapeutic vulnerability
for the tumor. The ability of EGFR and ALK inhibitors to stimulate this response in lung cancers driven
by mutant EGFR and ALK is clinically relevant considering their poor responses to immunotherapies
deployed as monotherapies. We propose that oncogenic RTKs such as EGFR, ALK, ROS1, and MET act
to suppress inflammation mediated by this innate immune response and thereby, actively contribute to
immune evasion, a hallmark of cancer. Treatment with TKIs counteract this suppression, thereby “releasing
the brake” on inflammatory signaling pathways and allowing for recruitment of effector immune cells and
increased antigen presentation [Figure 1]. This provides a mechanism to explain the connection between
an inflammatory phenotype and response to TKI. Although this TKI mediated release on inflammatory
suppression represents a novel vulnerability that may be capitalized on by treatment with IO, early
clinical data indicate that combining TKIs with existing IO exacerbates the frequency and degree of some
adverse events, especially pneumonitis, hepatitis, and pulmonary fibrosis. This calls for further preclinical
mechanistic studies to fully understand the impact of TKIs on the crosstalk between the TME and cancer
cells, as well as the effect on normal epithelial tissue function.