www.sciencemag.org SCIENCE VOL 344 11 APRIL 2014 149
edited by Jennifer Sills
LETTERS I BOOKS I POLICYFORUM I EDUCATION FORUM I PERSPECTIVES
Against great odds
Immunotherapy: It Takes a Village
WE IN THE CANCER IMMUNOLOGY AND IMMUNOTHERAPY COMMUNITY ARE THRILLED THAT
Science named “Cancer immunotherapy” as 2013’s Breakthrough of the Year (J. Couzin-Frankel, 20 December 2013, p. 1432). The rapid succession of clinical successes by blocking antibodies to two immune checkpoints, CTLA-4 and PD-1, and by
chimeric antigen-receptor-transduced T cells, shows the power of basic immunology when translated to therapy. As such, I write to acknowledge some of the
key scientists whose basic discoveries paved the way for the clinical successes
outlined in the Breakthrough issue.
CTLA-4 was originally cloned by Pierre Goldstein (1). Peter Linsley later
demonstrated that its ligands were B7.1 and B7.2, in fact the same as for the T
cell costimulatory receptor CD28 (2, 3). On the basis of in vitro studies, Jeffrey
Bluestone first suggested that, in contrast to CD28, CTLA-4 was an inhibitory
receptor (4). A year later, concurrent with similar in vitro findings from Jim
Allison (5), Arlene Sharpe and Tak Mak independently proved CTLA-4’s inhibitory function in genetic knockout mice (6, 7). These discoveries paved the way
for Allison’s seminal work demonstrating in murine tumor models that CTLA-4 blockade
induced antitumor responses, supporting its subsequent clinical development.
An independent sequence of discoveries paved the way for the clinical development of
PD-1/PD-L1 pathway blockers. Almost 10 years after the cloning of PD-1 by Tasuku Honjo
(8), Gordon Freeman demonstrated that its major ligand was another B7 family member
(9) that had been identified a year earlier by Lieping Chen (10). This ligand-receptor pair
was also an immune “checkpoint” but biologically very different from CTLA-4. Chen went
on to show that many human tumors up-
regulate PD-L1 (11), commonly as an adap-
tive response to γ-interferon produced by
antitumor T cells (12). He also showed that
expression of PD-L1 in cancer cells con-
ferred immune resistance that
could be abrogated by antibod-
ies that blocked the PD-L1/
PD-1 interaction, leading to
tumor regression in mouse
The origin of chimeric anti-
gen receptors dates back to
work by Zelig Eshhar (13), who
first demonstrated that trans-
duction of T cells with chime-
ric genes encoding single-chain
antibodies linked to a transmembrane region
and an intracellular domain. The intracel-
lular domain, encoding the signaling adap-
tor for the T cell receptor, was discovered by
Larry Samelson and Richard Klausner (14).
It could redirect T cell killing to cells express-
ing the antibody’s cognate antigen.
Eventually, millions of cancer patients
will benefit from these immunotherapies
and will hopefully be reminded by their physicians that they are the fruits of decades
of basic immunology research, which must
continue to be supported.
Abeloff Professorship in Oncology, Cancer Immunology and
Hematopoiesis Program, Sidney Kimmel Comprehensive
Cancer Center, Johns Hopkins University, School of
Medicine, Baltimore, MD 21287, USA. E-mail: dpardol1@
1. J. F. Brunet et al., Nature 328, 267 (1987).
2. P. S. Linsley et al., J. Exp. Med. 173, 721 (1991).
3. P. S. Linsley et al., J. Exp. Med. 174, 561 (1991).
4. T. L. Walunas et al., Immunity 1, 405 (1994).
5. M. F. Krummel, J. P. Allison, J. Exp. Med. 182, 459 (1995).
6. E. A. Tivol et al., Immunity 3, 541 (1995).
7. P. Waterhouse et al., Science 270, 985 (1995).
8. Y. Ishida et al., EMBO J. 11, 3887 (1992).
9. G. J. Freeman et al., J. Exp. Med. 192, 1027 (2000).
10. H. Dong et al., Nat. Med. 5, 1365 (1999).
11. H. Dong et al., Nat. Med. 8, 793 (2002).
12. J. M. Taube et al., Sci. Transl. Med. 4, 127ra37 (2012).
13. Z. Eshhar, T. Waks, G. Gross, D. G. Schindler, Proc. Natl.
Acad. Sci. U.S.A. 90, 720 (1993).
14. L. E. Samelson et al., Cell 43, 223 (1985).
Women in Engineering
M. Klawe’s Book Review about Girls Coming to Tech! by Amy Sue Bix (14 March, p. 1201)
recounts the challenges faced by women who pursued engineering before the 1970s. The
topic elicited personal accounts, including one by the woman shown in the Review’s photo.
See the comments below and at www.sciencemag.org/content/343/6176/1201.full.
I was delighted to see myself pictured in your article, at 17 and with a slide rule. My years at
MIT were full of memorable ups and downs. Though our numbers were small, there were more
women who loved math and science than I had ever known before. I met many of my closest
friends and colleagues during those years. I am now in my 43rd year as a professor at Northeastern University, where I was one of the founders of the College of Computer and Information Science. —Harriet Fell
While reading the text, some memories came to me. In 1990, during an interview for work
experience, a director of an international company told me “your CV is very good technically
speaking, but you have a problem: You are a woman.” However, today I am very happy with
my engineering work. —Vania Salvini