By Sangeeta Goswami1 and
T cells eliminate pathogens by recogniz- ing foreign proteins that are expressed on the cell surface (antigens). T cell ac- tivation in response to antigen occurs for a controlled period of time and is topped by the expression of immune
checkpoint proteins (1). Allison and colleagues proposed that antibody blockade of
these proteins would enable prolonged T cell
responses against cancer cells (2). The preclinical and clinical data that emerged using
antibodies against two immune checkpoint
proteins, cytotoxic T lymphocyte–associated
protein 4 (CTLA4) and programmed
cell death receptor–1 (PD-1), led to
a paradigm shift in oncology as the
treatment of some patients with these
drugs led to tumor regression and durable survival for more than a decade
(3). But as more patients with various types of cancer have been treated
with immune checkpoint therapies,
an enduring problem is to identify
which patients are likely to respond.
On page 409 of this issue, Le et al. (4)
report the response to anti–PD-1 therapy (pembrolizumab) in 12 different
tumor types, and show that patients
who responded to the agent had
defects in a DNA damage response
pathway called mismatch repair.
Mutations frequently arise in tumor cells and they are broadly divided into driver mutations and
passenger mutations, where the former are necessary for tumorigenesis
and the latter are considered bystanders resulting from accumulated DNA damage
that variably occurs in tumors (5). Elegant
work predicted that driver and passenger
mutations may generate mutated proteins
with the potential to be recognized as antigens (6). These tumor-associated neoantigens
can be processed and presented by antigen-presenting cells (APCs) and recognized by
T cells, activating anti-tumor immune responses (7) (see the figure).
In the hunt for biomarkers to predict
which patients would benefit from immune
checkpoint therapy, early studies indicated
that tumors with high mutation burdens
were more likely to respond because of their
propensity to produce neoantigens (8–10).
This idea was further corroborated when
only one of 33 patients with colorectal can-
cer responded to nivolumab (which targets
PD-1) in a phase 1 clinical trial (11). This pa-
tient, an exceptional responder, had defec-
tive mismatch repair. The mismatch repair
pathway recognizes and repairs errors in
DNA base pairing, which can lead to muta-
tions. Defects in the mismatch repair path-
way occur in Lynch syndrome, an inherited
cancer-associated syndrome (12), as well as in
various sporadic cancers. On average, tumor
cells harboring mismatch repair defects have
more than 1000 mutations, whereas tumor
cells without mismatch repair defects have
fewer than 100 mutations (13).
These observations led to a phase 2 clini-
cal trial (14), involving the same group as
Le et al., which showed strong association
of mismatch repair defects with response to
pembrolizumab. Hence, the current “basket
trial” was initiated in which Le et al. evalu-
ated the response to pembrolizumab in pa-
tients whose tumors harbor mismatch repair
deficiency irrespective of tissue of origin. The
study enrolled 86 patients with progressive
disease comprising 12 different cancer types,
all with mismatch repair defects. Objective
responses (where tumor size was reduced)
were noted in 53% of patients, and 21%
achieved complete response (where tumors
were no longer detectable). Primary resis-
tance to pembrolizumab was noted in 14%
of patients, and acquired resistance (when
tumors initially respond and then regrow
while receiving treatment) was noted in ~6%
of patients. Using a neoantigen prediction al-
gorithm, they found that the top 15 neoanti-
gens expressed by tumor cells that respond to
pembrolizumab probably result from defec-
tive mismatch repair. Further investigation
suggests that immune checkpoint blockade
might expand neoantigen-specific T cells,
leading to tumor immunity.
These findings strongly suggest that
mismatch repair deficiency—which is
caused by genetic defects that affect
the proteins involved in the mismatch
repair pathway—can be used as a biomarker to identify patients regardless
of the tumor origin. These data also
emphasize the relevance of basket trials to test a drug on the basis of tumor genetics rather than the organ in
which they occur. This trial has led the
U.S. Food and Drug Administration to
approve the use of pembrolizumab for
tumors with mismatch repair defects,
even if it is not approved for that specific tumor type. For example, pembrolizumab is not approved to treat
prostate cancer, but patients with
mismatch repair–defective prostate
cancer can now be treated with pembrolizumab. It is imperative to identify biomarkers to guide appropriate
patient selection for immune checkpoint therapy and to continue to integrate
cancer genetics with immunology. j
1. T.L.Walunas et al., Immunity1, 405(1994).
2. D. R. Leach, M. F. Krummel, J. P. Allison, Science 271, 1734
3. P. Sharma, J. P. Allison, Science 348, 56 (2015).
4. D. T. Le et al ., Science 357, 409 (2017).
5. B. Vogelstein et al., Science 339, 1546 (2013).
6. N. H. Segal et al ., Cancer Res. 68, 889 (2008).
7. T. N. Schumacher, R. D. Schreiber, Science 348, 69 (2015).
8. N.A.Rizvi etal.,Science 348,124(2015).
9. A.Snyder et al., N. Engl. J. Med. 371,2189(2014).
10. E. M. Van Allen et al ., Science 350, 207 (2015).
11. S.L. Topalian et al., N. Engl. J. Med. 366,2443(2012).
12. K. W.Kinzler,B.Vogelstein, Cell 87,159(1996).
13. J. R. Eshleman et al ., Oncogene 10, 33 (1995).
14. D. T.Le etal.,N.Engl.J.Med. 372,2509(2015).
Genetic biomarker for cancer immunotherapy
A tumor-associated defect can identify patients to receive immune checkpoint therapy
1Department of Genitourinary Medical Oncology, University
of Texas MD Anderson Cancer Center, Houston, TX, USA.
2Department of Immunology, University of Texas M. D.
Anderson Cancer Center, Houston, TX, USA.
to T cells.
Activating T cells
INSIGHTS | PERSPECTIVES
Mutations as antigens
Mismatch repair deficiency in tumor cells can be used as a biomarker
for immune checkpoint therapy. TCR, T cell receptor; MHC, major