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its ligands (NKG2DL) are commonly expressed by tumors. Tumor cells however can also express NKG2D
and hijack NKG2DL signaling to drive stem-cell like behavior [170] . NK cells participate in tumor-induced
polarization, acquiring a pro-tumorigenic and pro-angiogenic phenotype [171] .

Dammeijer et al. [172] provide a thorough review of primary and secondary resistance mechanisms
[80]
and treatment options for re-sensitizing tumors. Guo et al. provide a compact review of the wide
variety of immunosuppressive mechanisms employed by tumors. Chen and Mellman [173] describe
these mechanisms in the context of the cancer immunity cycle. A concise table of many elements that
underlie tumor escape is given by Accolla and Tosi [174] . Seliger [150] and Seliger et al. [175] review MHC-I
and MHC-II-based evasion mechanisms, respectively. A report of HLA allele-specific risk of metastasis
in papillary thyroid cancer [176] provides evidence that MHC allele status impacts cancer progression.

Frameworks for understanding tumor-immune system interactions
Reducing therapeutic resistance is closely tied to our understanding of how cancer arises in the context of
the immune system, which we briefly discuss here. The primary framework for understanding the interplay
between cancer and the immune system is known as immunoediting [177] . This posits that selection pressure
from the immune system “edits” the tumor, forcing it to find a custom response to the local and systemic
state of the immune system in order to escape immune pressure after many years of genetic changes.

Therapeutic success is often defined by reduction in the incidence and impact of metastatic cancer. The
origin and nature of metastases is a dynamic research area, with much remaining to be discovered. Do
metastases represent dissemination of cancer cells from a primary tumor in late stage disease (Halsted-
Meyer theory) [178] , or do they reflect the outgrowth of pre-existing cells that disseminated early on
[Figure 3] [179] ? TNM staging [180] encourages the former perspective. Weichselbaum and Hellman [181] posit
the existence of cancers with intermediate metastatic potential. The hypothesis of cancer dormancy
posits that tumor cells may disseminate early and are forced into dormancy in order to survive immune
surveillance [182,183] . From this perspective, one goal of immunotherapy is to keep such cells dormant, as
opposed to attempting to eliminate them all [184,185] . Such topics have been covered in a chapter-length review,
including the different kinds of dormancy, the role of circulating tumor cells and of innate and adaptive
immune cells, and ideas for keeping dormant tumor cell indolent [186] . It is evident that this research area is
both difficult and in its early stages.

NEXT STEPS
A number of authors have sought to identify the most urgent and interesting near-term trends.
Whiteside et al. [187] and Hoos [188] foresee a focus on, amongst other topics, understanding PD-1
nonresponders, targeting the tumor microenvironment, improving therapy of tumors with few mutations or
low tumor infiltrating lymphocyte count, better tumor and patient assessments, combination therapies, and
biomarkers of response. This includes the proposed acknowledgment that stable chronic disease (“functional
cure”) is a worthwhile endpoint.

Combination therapy is hailed as possibly the best way to increase the percentage of responders. Current
examples of combination therapy tend to have a reactive character, applying an additional therapy in
response to failure of an initial one. A strong call was issued in 2015 for increased funding of trials to study
how to combine molecularly targeted and immuno-therapies [189] .

In general, it is hoped that progress can be made through examination of rational combinations [172] . The
meaning of “rational synergy” has been dissected in the context of cytotoxic drug combinations [190] . The
diversity of currently available modalities may allow combinations where treatments are carefully scheduled
to act as e.g. “mutual adjuvants”. Adjuvants [191-193] continue to be topics of active research, with the line