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Treatment with oncogene specific TKIs induces tumor/epithelial cell-autonomous expression of MHC class
I and II involved in antigen presentation, CXCL10 involved in effector immune cell recruitment and IL6,
TGFB2 and CCL28 which recruit and activate immune suppressive cell types. This inflammatory phenotype
represents a normal physiological response in normal epithelial cells and is retained in carcinoma cells
providing a link between normal epithelial cell homeostasis and tumor therapeutic response. These proteins
and factors are postulated to instruct both pro- and/or anti- tumorigenic immune cells and contribute to the
degree of therapeutic response observed in patients with lung cancer driven by oncogenic RTKs.

In addition to engaging in paracrine communication with the TME through activation of an IFN like response,
EGFR inhibitors also have the potential to influence immune responses by modulating MHC expression and
antigen presentation. In the context of cancer immunology, MHC molecules govern interactions between
tumor cells and CD4 and CD8 positive T cells by functioning as antigen presenting machinery for tumor
specific antigens. Pollack et al. , Kersh et al. and Pollack demonstrated that treatment with multiple
[30]
[31]
[29]
EGFR TKIs and cetuximab enhanced the induction of MHCI and MHCII seen when primary keratinocytes
and malignant keratinocyte A431 cells were treated with IFNγ. Skin biopsies from patients treated with
and EGFR inhibitor also demonstrated an increase in epidermal MHCI expression. This response was also
observed with erlotinib, cetuximab, and the pan-ErbB inhibitor, dacomitinib, in head and neck cancer cell
lines [32,33] . Interestingly, this EGFR inhibitor-mediated induction of MHCI was observed in the absence of
IFNγ. These findings support a role for EGFR not only in immune surveillance via immune cell recruitment,
but also in immunoediting through increased antigen presentation.

ROLE OF THE TUMOR IMMUNE MICROENVIRONMENT IN DICTATING IMMUNOTHERAPY
RESPONSE
Inflammation characterized by expression of genes that drive immune cell infiltration has recently come to
light as being important in response to immune-oncology (IO) drugs that inhibit the PD1-PDL1 immune
checkpoint. Clinical benefit has been observed in carcinomas of the lung, head and neck, and skin, however
patients who are never smokers (i.e., ALK, ROS, and RET positive lung tumors) or whose tumors express
mutant EGFR, whether PD-L1 positive or negative, have not experienced benefit . In ALK and EGFR
[35]
mutant lung cancer patients whose tumors tested high for PD-L1, overall response rate following durvalumab
treatment was only 0%-14%. These data suggest that some patients within these cancer subgroups may exhibit
innate resistance to immunotherapy agents, despite the presence of PD-L1 positivity. To this end, Gajewski
and colleagues have proposed that T cell inflammation within the TME serves as a superior predictive marker
of sensitivity to immunotherapy, and that tumors with scant T cell inflammation exhibit poor responses
consistent with innate resistance [36-38] . In this context, T cell inflammation is associated with activation of
IFN response pathways. As support of this, Ayers et al. and colleagues report an IFNγ signature that
[39]
predicts response to anti-PD1 better than PD-L1 positivity, alone, across multiple cancers.

Despite some evidence for modestly increased response rates in early trials with combinations of TKIs
and IO agents in lung cancer patients, there are tolerability and safety challenges arising as a result of
severe toxicities . Based on the results of recent trials, combining these two treatment modalities is
[40]
predicted to yield enhanced frequency and grade of on-target side effects. In support of this, the TATTON
trial [Table 1], a multi-arm phase Ib trial investigating osimertinib in combination with durvalumab in
patients with EGFR mutant NSCLC, reported an increase in ILD with the combination compared to either
drug alone . Likewise, the phase I CheckMate012 trial with erlotinib in combination with nivolumab in
[41]
EGFR mutant patients reports incidences of discontinued treatment due to pneumonitis as well as hepatic
toxicities [42,43] . Furthermore, the CheckMate370 trial, a single arm study to evaluate the safety of nivolumab
in combination with crizotinib in patients with ALK positive NSCLC, also reported incidence of severe and
fatal hepatic toxicities . Collectively, the early results from these trials indicate that combining TKIs with
[44]