Page 24 - Read Online

Tokuyasu et al. J Cancer Metastasis Treat 2018;4:2 I http://dx.doi.org/10.20517/2394-4722.2017.52 Page 5 of 24

The idea that one clonal TCR recognizes one specific antigen has been supplanted by the notion that TCRs
[25]
are cross-reactive. A discussion of how TCRs must be cross-reactive in principle is given by Sewell .
Indeed, TCR recognition that straddles the self/non-self boundary (e.g. between self and microbial peptides)
underlies the theory of molecular mimicry, whereby bacterial antigens do not provoke attack or conversely
[26]
may lead to autoimmune disease . The specific mechanisms are now being worked out [27,28] . Similarly,
mutant tumor proteins may avoid immunogenicity by being cross-reactive with self-proteins.

Each individual’s immune system will also have peptides that it cannot recognize, which can be characterized
as “holes” or “blind spots”. These can arise both from gaps in presentation (lack of peptide-MHC binding)
[29]
or recognition (absence from the TCR repertoire) . A vaccine based solely on an antigen in such a hole
will not work for that individual. Such phenomena are seen in the context of microbial immunity [30,31] . The
[32]
concept of original antigenic sin states that such a hole can paradoxically be created by initial exposure to
an antigen, as the immune system does not mount a novel response when it encounters a slight variant.

+
Immunological research continues to reveal new features. Activated CD8 T cells were found to require cross
presentation, i.e. co-stimulation by dendritic cells that can present exogenous antigens on MHC-I, for full
[35]
induction of cytotoxic response [33,34] . The CD4 lineage was resolved into four lines and then a plastic set of
[36]
+
more . Some CD4 T cells can acquire cytotoxic activity [37,38] (i.e. not only CD8 T cells can be cytotoxic).
+
[39]
More recently, a “second touch hypothesis” suggests that the high-level picture for polarization of T cells
[40]
may not yet be complete. New immune cell subtypes continue to be discovered . As one consequence,
mathematical modeling of the immune system is likely to remain a difficult endeavor for some time.
We mention here briefly the once-dominant view of cancer as an autonomous genetic disease, as captured
[41]
by the original “hallmarks of cancer” . The cancer phenotype arises as a result of selection pressure on
genome mutations, leading to acquisition of limitless growth and survival potential, with genome instability
as an “enabling characteristic”. These mechanisms also underlie cancer’s uncanny ability to acquire additional
phenotypes such as eliciting immune tolerance and angiogenesis. A recent proposal that epigenetics alone
[42]
may be sufficient to generate the hallmarks of cancer may, amongst other things, alter our understanding
[43]
of the time scales involved in tumor response .
The careful examination of tumor cell evolution and its therapeutic implications are in its beginning
[48]
stages [44-47] . Principles such as antagonistic pleiotropy , where reproductive fitness in youth is played off
against fitness in old age, are also sometimes raised as setting fundamental biological limits.

For further background on cancer and immunology, the reader can consult reference books [49,50] , a three-
[52]
[51]
volume series , and a broad history from a contrarian perspective .
RECENT DEVELOPMENTS IN CANCER IMMUNOTHERAPY
Modalities of T-cell based immunotherapy
The design of currently popular T-cell based immunotherapies can be described as follows:
[53]
• Release the brakes: checkpoint blockade ;
• Boost instruction, via antigens: cancer vaccines;
• Boost instruction, via cell transfer, bypassing presentation: adoptive dendritic cell therapy [54,55] ;
[56]
• Boost recognition, via cell transfer, bypassing instruction: adoptive T cell therapy ;
• Boost recognition, via cell transfer, bypassing instruction and MHC restriction: adoptive chimeric
antigen receptor T-cell (CAR-T) therapy [57,58] .

All of these therapies are based on T cells. Checkpoint blockade therapy is distinguished by not targeting
cancer, relying instead on the host immune system training (or having already trained) itself to target tumors.